The use of TAAR1 agonists such as ulotaront, deprenyl or benzofuranylpropylaminopentane to increase dopamine in the retina to treat ocular disorders

Abstract

Trace amine-associated receptor 1 (TAAR1) agonist compounds are provided for the treatment of ocular disorders. The mechanism of enhancer compounds is to increase retinal dopaminergic activity, which may restore BDNF / VEGF balance required for healthy vision. The compounds may be used per se or in combination with anti-VEGF medications (e.g. aflibercept, ranibizumab, bevacizumab) for treatment of retina diseases such as macular degeneration, diabetic retinopathy, and other neurodegenerative disorders claimed.

Description

Treatment of ocular disorders associated with decreased dopaminergic activity FIELD OF THE INVENTIONThe invention relates to trace amine-associated receptor 1 (TAAR 1) agonist compounds, in particular dopaminergic activity enhancer compounds for use in the treatment of neurodegeneration-related retinal pathologies. The invention also relates to pharmaceutical preparations, in particular topical administration of eye drops, ointments, inserts, implants or intravitreal injection containing the enhancer compounds in hitherto unused low concentrations. These preparations assure constant concentrations of the enhancer compounds in the posterior segment of the eye in order to maintain TAAR1 -mediated dopamine release from retinal amacrine cells. Enhanced dopamine levels restore the BDNF / VEGF disbalance in the retina and exert curative effects in neurodegenerative retinal disorders. When combined, enhancer compounds and / or TAAR1 agonist compounds potentiate anti-VEGF medications to restore impaired BDNF / VEGF equilibrium observed in such retinal pathologies.BACKGROUND OF THE INVENTIONIt was more than sixty years ago that selegiline ((-)-L-deprenyl, N-methyl~;V-(2- propinyl)-2-methyl-l-phenylethylamine), the compound that later became the first known selective B type monoamine oxidase (MAO) inhibitor, was synthesized [Knoll and Magyar, 1972], The possible therapeutic use of selegiline was obscure until the mid-seventies when it became evident that the compound exerts L-DOPA-sparing effects and it turned into a standard element of the treatment of Parkinson’s disease [Birkmayer et al., 1977], In search of selegiline’s mode of action, a series of analogue compounds has been synthesized. In one direction, novel chemical synthetic works have been initiated to obtain compounds containing the propargyl group, that was considered responsible for MAO inhibition, attached to various aryl groups [Magyar et al., 1979],In another direction, a series of aryl -substituted 2-propyl-aminopentanes was synthesized [Knoll et al., 1999], Since 2-propyl-aminopentanes do not contain propargyl residuum, these molecules do not possess MAO-B inhibitory properties. A number of these compounds was, however, capable of increasing the electrical stimulation-induced release of catechol- and indoleamines in low femto / picomolar concentrations in in vitro conditions without altering the resting release of thesebiogenic amines [Knoll et al., 1998], Compounds exhibiting these unique pharmacological actions are designated as catecholaminergic activity enhancer (CAE) drugs. The most widely investigated drugs of this series are (-)PPAP ((-)-l-phenyl-2-propylaminopentane) and its indole ((-)IPAP, (-)-l-(indol-3-yl)-2-propylaminopentane) and benzofuran ((-)BPAP (( / ?)-(-)- 1 -(benzofuran -2-yl )-2-propylaminopentane) analogues (Figure 1). An important step-through was the demonstration that selegiline exhibits enhancer effects in a number of behavioral tests [Miklya, 2014; Harsing et al., 2023],Early pharmacological investigation of deprenyl revealed differences of the enantiomers in their mode of action: whereas L-deprenyl was more effective in MAO inhibition than D-deprenyl, the latter proved to be more effective in inhibition of dopamine uptake in rat brain synaptosomes [Magyar et al., 1967; 2004], It is worth mentioning that the catecholaminergic (dopaminergic) activity enhancer effect of selegiline is not related to its MAO-B inhibitory or other effects (antiapoptotic, scavenger, superoxide dismutase activity inhibition) and appears in magnitudes lower concentrations.In the retina, a type of amacrine cells is the source of the dopamine released. Dopamine-containing neurons are interneurons and belong to the amacrine cells located in the inner nuclear layer (INL) of the retina (Figure 2). These cells form two distinct groups: the dopamine-containing interamacrine cells, which make synapses with other amacrine cells, and the dopamine-containing interplexiform cells, which synapse to horizontal, bipolar, and other amacrine cells [Hadjiconstantinou et al., 1988; Djamgoz and Wagner, 1992], Some dopaminergic amacrine cells (Al 8) also contain GABA as co-transmitter. Dopaminergic amacrine cells receive inputs from the rod and cone pathways relayed via bipolar cells and a subgroup of retinal ganglion cells [Newkirk et al., 2013], The interneural communication of dopaminergic amacrine cells is mediated by stimulatory dopamine DI and the inhibitory dopamine D2 receptor families in the retina [Flood and Eggers, 2021], A subtype of ganglion cells also secretes dopamine and we assume that selective loss of these cells in the ganglion cell layer may have pathological importance in a subset of glaucomatous retinopathies characterized by an impaired retinal dopaminergic neurotransmission [Liang et al., 2023],Dopamine-containing amacrine cells are light-activated as they receive inputs from rod and cone photoreceptors (Figure 3). Light stimulates dopamine synthesis in retinalamacrine cells as it increases activity of aromatic amino acid decarboxylase (AADC), an enzyme responsible for conversion of L-DOPA to dopamine [Hadjiconstantinou et al., 1988],Dopaminergic neurons are thus different in the brain and in the retina: the dopaminergic neurons of e.g. the brain stem and the stratum are projection neurons, while the dopaminergic amacrine cells of the retina are light-activated interneurons. There are no data on the enhancer effect of selegiline or indeed any enhancer compound on the dopaminergic cells of the retina similar to that on the dopaminergic cells of the brain.Almost parallel in time as the enhancer drugs were published, two laboratories have independently described a specific binding site for the trace amines phenylethylamine, tyramine, and tryptamine [Borowsky et al., 2001; Bunzow et al., 2001], This binding site was designated as trace amine-associated receptor (TAAR). Of the different isoforms, TAAR1 is probably the most widely investigated in neural tissues [Gainetdinov et al., 2018], The presence of TAAR1 was demonstrated in brain nuclei containing cell bodies of noradrenergic, dopaminergic, and serotonergic neurons and in projection brain areas such as the cerebral cortex, olfactory bulb or caudate nucleus [Xie et al., 2007; 2009], TAAR1 may have a key role in regulation of events in dopaminergic axon terminals, like direction of transporter operation, autoreceptor-mediated feedback inhibition, and neurotransmitter release with cytoplasmic or vesicular origins [Miller, 2011; Harsing et al., 2022],There are no data showing the presence of TAAR1 in the retina.Trace amines are the endogenous ligands for TAAR1 and synthetic ethylamine derivatives, like the enhancer compounds, serve as exogenous agonists for TAAR1 [Grandy, 2010], Many of the synthetic compounds are optically active thus, their pharmacological activity on TAAR1 is stereospecific and may be related to their dopamine uptake inhibitory potential [Lewin et al., 2011],Light input also increases activity of AADC involved in the conversion of amino acids (phenylalanine, tyrosine, tryptophan) to trace amines (phenylethylamine, tyramine, tryptamine). Trace amines are produced in D cells in the central nervous system. D cells have not been identified in retinal circuits [Mura et al., 1995],In physiological conditions, dopamine released from retinal amacrine cells is involved among others in vision acuity, regulation of light-adaptive vision, colour perception, and recognition of contrast sensitivity [Witkovsky, 2004], High levels of dopamineoccur in the retina during the day and low levels can be detected at night indicating that adaptation from dim light to day light depends on amacrine cell dopamine [Doyle et al., 2002], Retinal dopamine also plays a role in the circadian clock function of the eye [Besharse and McMahon, 2016],Dopaminergic activity in the retina and visual function is presumably reduced in aging. Moreover, dopamine depletion in the retina leads to impaired light adaptation [Malmfors, 1963; Hadjiconstantinou and Neff, 1984], Decreased dopaminergic activity in the retina also occurs in different vision pathologies. In Parkinson’s disease, when the number of dopaminergic amacrine cells is reduced, low retinal dopamine levels lead to disturbed vision and impaired contrast recognition [Suleiman et al., 2023], In our experimental model, the dopamine neurotoxin 6-hydroxydopamine pretreatment abolished [3H]dopamine release from rat retina (unpublished data). In addition, early retinal dysfunction in diabetic retina is reversible using L-DOPA treatment suggesting that reduced retinal dopamine underlines visual deficit in diabetes mellitus [Motz et al., 2020], Thus, it can be concluded that a series of ocular disorders is associated with decreased dopaminergic activity in the retina.SUMMARY OF THE INVENTION A TAAR1 agonist compound is provided for use in the treatment or prevention of an ocular disorder associated with a decreased dopaminergic activity or decreased dopamine release in the eye. A method is provided for the treatment or prevention of an ocular disorder associated with a decreased dopaminergic activity or decreased dopamine release in the eye, comprising administering an effective amount of a TAAR1 agonist compound to a patient in need thereof.A TAAR1 agonist compound is provided for use in the treatment or prevention of an ocular disorder associated with a decreased dopaminergic activity or decreased dopamine release in the eye by restoring the physiological balance between brain-derived neurotrophic factors (BDNF) and vascular endothelial growth factor (VEGF) in the eye. A method is provided for the treatment or prevention of an ocular disorder associated with a decreased dopaminergic activity or decreased dopamine release in the eye by restoring the physiological balance between BDNF and VEGF in the eye, comprising administering an effective amount of a TAAR1 agonist compound to a patient in need thereof.A TAAR1 agonist compound is provided for use in the treatment or prevention of an ocular disorder associated with an impaired balance of the activities of BDNF and VEGF in the eye. A method is provided for the treatment or prevention of an ocular disorder associated with an impaired balance of the activities of BDNF and VEGF in the eye, comprising administering an effective amount of a TAAR1 agonist compound to a patient in need thereof.A TAAR1 agonist compound is provided for use in the treatment or prevention of an ocular disorder associated with a decreased activity or expression of BDNF in the eye. A method is provided for the treatment or prevention of an ocular disorder associated with a decreased activity or expression of BDNF in the eye, comprising administering an effective amount of a TAAR1 agonist compound to a patient in need thereof.A TAAR1 agonist compound is provided for use in the treatment or prevention of an ocular disorder associated with an increased activity or expression of VEGF in the eye. A method is provided for the treatment or prevention of an ocular disorder associated with an increased activity or expression of VEGF in the eye, comprising administering an effective amount of a TAAR1 agonist compound to a patient in need thereof.A TAAR1 agonist compound is provided for use in the treatment or prevention of an ocular disorder associated with a decreased dopaminergic activity or decreased dopamine release in the eye by decreasing the expression or the activity of VEGF in the eye. A method is provided for the treatment or prevention of an ocular disorder associated with a decreased dopaminergic activity or decreased dopamine release in the eye by decreasing the expression or the activity of VEGF in the eye, comprising administering an effective amount of a TAAR1 agonist compound to a patient in need thereof.A TAAR1 agonist compound is provided for use in the treatment or prevention of an ocular disorder associated with a decreased dopaminergic activity or decreased dopamine release in the eye by increasing the expression or the activity of BDNF in the eye. A method is provided for the treatment or prevention of an ocular disorder associated with a decreased dopaminergic activity or decreased dopamine release in the eye by increasing the expression or the activity of BDNF in the eye, comprising administering an effective amount of a TAAR1 agonist compound to a patient in need thereof.A pharmaceutical composition is provided, comprising a TAAR1 agonist compound and at least one pharmaceutically acceptable carrier or excipient, wherein the pharmaceutical composition is for intraocular administration.Preferably the ocular disorder is a retinal disease.Preferably the disorder is associated with a decreased dopaminergic activity or decreased dopamine release in the retina.Preferably the physiological balance between BDNF and VEGF is restored in the retina or the impairment of the balance of the activities of BDNF and VEGF in the retina is mitigated.Preferably the disorder is associated with a decreased activity or expression of BDNF in the retina.Preferably the disorder is associated with an increased activity or expression of VEGF in the retina.Preferably the expression or the activity of VEGF is decreased in the retina by the TAAR1 agonist compound.Preferably the expression or the activity of BDNF is increased in the retina by the TAAR1 agonist compound.Preferably the TAAR1 agonist compound is a compound of Formula (I)whereinRi and R2 are each independently hydrogen or C1-C4 alkyl,R3 and R4 are each independently hydrogen or C1-C4 alkyl,R5 and Re are each independently hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, mono-or di-(Cl-C4 alkyl)amino, phenyl, or 5- or 6-membered aliphatic or aromatic heterocycle containing 1 or 2 heteroatoms selected from N, O, S,or pharmaceutically acceptable salt or stereoisomer thereof.Preferably the TAAR 1 agonist compound is a compound of Formula (la)whereinRi and R2 are each independently hydrogen or C1-C4 alkyl,R3 and R4 are each independently hydrogen or C1-C4 alkyl,R5 and Rs are each independently hydrogen, halo, or C1-C4 alkyl,or pharmaceutically acceptable salt thereof.Preferably the compound is ulotaront.Preferably the TAAR1 agonist compound is a dopaminergic activity enhancer compound according to Formula (II)whereinQ is a group consisting of a substituted or unsubstituted, aromatic, six-membered ring which may or may not have one or two heteroatoms,orQ is a substituted or unsubstituted bicyclic group which consists ofa benzene ring and, fused to said benzene ring,a saturated or unsaturated five- or six-membered ring which may or may not have one to three, preferably one to two heteroatom(s)wherein if Q is substituted,said substituent is selected from the group consisting of hydrogen, hydroxyl, Cl -4 alkyl, Cl -4 alkoxy and halogen, preferably Q is substituted with one or two substituent(s) or is unsubstituted,Ri is Cl -5 alkyl, preferably Cl -4 alkyl, preferably methyl, ethyl or propyl;R.2 is hydrogen, Cl -4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 alkylcarbonyl, C6-10 aryl or C7-11 arylalkyl;R3 is hydrogen, methyl or ethyl,or pharmaceutically acceptable salt or stereoisomer thereof.PreferablyQ is a group consisting of a substituted or unsubstituted, aromatic, six-membered ring which may or may not have one or two heteroatoms,wherein if Q is substituted,said substituent is selected from the group consisting of hydrogen, hydroxyl, Cl -4 alkyl, Cl -4 alkoxy and halogen, preferably Q is substituted with one or two substituent(s) or is unsubstituted,Ri is a Cl -5 alkyl, preferably is methyl, ethyl or propyl;R2 is Cl -4 alkyl, C2-4 alkenyl or C2-4 alkynyl;R3 is hydrogen, methyl or ethyl.Preferably Q is an unsubstituted aromatic, six-membered ring and preferably wherein Q is a phenyl group and Ri is methyl, ethyl or propyl and R2 is C2-3 alkyl, C2-3 alkenyl or C2-3 alkynyl, preferably R2 is ethynyl and an R3 is hydrogen or methyl. Preferably the compound according to Formula (II) is a compound according to Formula (III)wherein Q is phenyl andRi is methyl, ethyl or propyl;R2 is methyl, ethyl, ethynyl or propyl, preferably ethyl or ethynyl;R3 is hydrogen, methyl or ethylor pharmaceutically acceptable salt or stereoisomer thereof.Preferably Q is phenyl andRI is methyl, ethyl or propyl;R2 is ethyl or ethynyl;R3 is hydrogen or methyl.Preferably the compound is l-Phenyl-2-propylaminopentane (PPAP), preferably (R)-l-Phenyl-N-propylpentan-2-amine ((-)-PPAP), preferably (+)-PPAP, preferably a (racemic) mixture of (-)-PPAP and (+)-PPAP.Preferably the compound is 7V-methyl-l-phenyl-7V-prop-2-ynylpropan-2-amine (deprenyl), preferably (7?)-7V-methyl-7V-(l-phenylpropan-2-yl)prop-2-yn-l -amine (Selegiline or (-)-Deprenyl), preferably (+)-D-deprenyl, preferably a (racemic) mixture of (-)-Deprenyl and (+)-D-Deprenyl.Preferably Q isa substituted or unsubstituted bicyclic group which consists ofa benzene ring and, fused to said benzene ring,a saturated or unsaturated five- or six-membered ring which may or may not have one to three, preferably one to two heteroatom(s) wherein if Q is substituted,said substituent is selected from the group consisting of hydrogen, hydroxyl, Cl -4 alkyl, Cl -4 alkoxy and halogen, preferably Q is substituted with one or two substituent(s) or is unsubstituted,Ri is Cl -5 alkyl, preferably Cl -4 alkyl, preferably methyl, ethyl or propyl;R2 is hydrogen, Cl -4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 alkylcarbonyl, C6-10 aryl or C7-11 arylalkyl;R3 is hydrogen, methyl or ethyl.Preferably Q is substituted with one or two substituent(s) or is unsubstituted, Ri is Cl -5 alkyl, preferably Cl -4 alkyl or C2-5 alkyl, preferably ethyl or propyl; R2 is hydrogen, Cl-4 alkyl, C2-4 alkylcarbonyl, C6-10 aryl or C7-11 arylalkyl;R3 is hydrogen, methyl or ethyl.Preferably Q is a substituted or unsubstituted bicyclic group which consists of one benzene ring and a saturated or unsaturated five- or six-membered, preferably fivemembered, ring which may or may not have one or more heteroatom(s), wherein if Q is substituted,said substituent is selected from the group consisting of hydrogen, hydroxyl, Cl-4 alkyl, preferably Cl -3 alkyl, Cl-4 alkoxy and halogen, preferably Q is substituted with one or two substituent(s) or is unsubstituted,Ri is a Cl -5 alkyl;R2 is hydrogen, C2-5 alkyl, C6-10 aryl or C7-11 arylalkyl, preferably C2-5 alkyl; R3 is hydrogen, methyl or ethyl.Preferably the one or more heteroatom(s) in Q is(are) selected from O and N, preferably one or two heteroatom(s) is(are) selected from O and N, and / or wherein Q is unsubstituted and Ri is propyl and R2 is ethyl, and / or whereinQ is selected from naphtyl, indolyl, benzofuranyl or 1,3-benzodioxolyl.Preferably Q is a substituted or unsubstituted bicyclic group which consists of one benzene ring and a saturated or unsaturated five-membered ring which has one or more heteroatom(s), preferably N or O, more preferably one N or one O.Preferably the compound is l-(lH-indol-3-yl)-N-propylpentan-2-amine (IPAP), preferably (R)-(-)-l-(indol-3-yl)-2-propylamino-pentane [(-)-IPAP], preferably (+)-IPAP, preferably a (racemic) mixture of (-)-IPAP and (+)-IPAP.Preferably the compound is a compound according to Formula (IV)wherein Ri is a C2-4 alkyl, preferably ethyl or propyl;R2 is hydrogen, Cl-3 alkyl, C2-3 alkylcarbonyl or C6-10 aryl;R3 is hydrogen, methyl or ethyl, preferably hydrogen,or pharmaceutically acceptable salt or stereoisomer thereof.Preferably the compound is benzofuranylpropylaminopentane (BPAP), preferably (2R)-1-(1 -benzofuran -2 -yl)-N-propylpentane-2-amine [(-)-BPAP], preferably (+)-D-BPAP, preferably a (racemic) mixture of (-)-BPAP and (+)-BPAP.Preferably the TAAR 1 agonist compound is a compound of Formula (V)(V),wherein X is CR; R is hydrogen, halogen or Cl -7 alkyl;L is a bond, -C(O)- or -C(O)NH-;Ar is phenyl or a five or six membered heteroaryl group, containing one or two N atoms;R1is halogen, Cl -7 alkyl, Cl -7 alkyl substituted by halogen, Cl -7 alkoxy, Cl -7 alkoxy substituted by halogen or cycloalkyl;n is 0, 1, 2 or 3;or pharmaceutically acceptable stereoisomer or salt thereof.Preferably the TAAR 1 agonist compound is ralmitaront.Preferably the dopaminergic activity enhancer compound is administered in a dose that provides a dopaminergic activity specific enhancer effect. Preferably the TAAR1 agonist compound is administered in a dose that provides a specific dopaminergic activity enhancer effect.Preferably the TAAR1 agonist compound is used in a dosage form that provides a concentration of the compound in the eye, preferably in the posterior segment of the eye, preferably in the retina that provides a specific dopaminergic enhancer effect. Preferably the concentration that provides a specific dopaminergic enhancer effect is 10"12-10"8mol / 1. Preferably the concentration of the TAAR1 agonist compound in the eye (or in cases of a retinal disease in the retina) is in the femto / pico / nanomolar range, preferably in the nanomolar range, more preferably in the picomolar range and more preferably in the femtomolar range. Preferably the concentration of the TAAR1 agonist compound in the eye (or in cases of a retinal disease in the retina) is 1 O'12- 1 O'9mol / L, preferably 10'u-10'9mol / L, preferably 10'10-10'9mol / L, preferably 1O'12-1O'10mol / L, preferably 1O'12-1O'10mol / L.Preferably the TAAR 1 agonist compound is formulated for ocular administration. A formulation for ocular administration may be eye drops, an eye cream, eye gel, eye mist, insert in conjunctival sac, scleral or intravitreal implant or intravitreal injection, a solution or suspension to be administered into the eye. The TAAR1 agonist compound may be formulated for parenteral local or systemic administration. The TAAR1 agonist compound may be formulated for oral administration.Preferably the TAAR1 agonist compound is formulated into a liquid pharmaceutical composition, preferably an eyedrop or insert, implant, intravitreal injection, and is administered in a dose of 10'12-10'9mol / L, preferably 10'u-10'9mol / L, preferably 10"10-10'9mol / L, preferably 1 O'12- 1 O'10mol / L, preferably 1 O'12- 1 O'10mol / L.The pharmaceutical composition comprising the TAAR1 agonist compound as defined in the specification prepared as an eye drop or other topically applied preparations, preferably insert, implant or intravitreal injection, may contain the compounds in concentrations of 0.01-1000 ng / ml, preferably 0.1-100 ng / ml, whereinthe estimated volume or weight of an eye drop is 50 pl or 50 pg. This pharmaceutical composition prepared as intravitreal injection may contain the TAAR1 agonist compound in a concentration of 0.01-1000 ng / ml, preferably 0.1-100 ng / ml solution with an injectable volume of 50 pl.Preferably the ocular disorder is a disorder which benefits from the increase of dopaminergic activity / dopamine release in the eye.Preferably, the decreased dopaminergic activity / dopamine release or the impaired balance of the activities of BDNF and VEGF or the decreased activity or expression of BDNF or the increased activity or expression of VEGF is a decreased dopaminergic activity / release or an impaired balance of the activities of BDNF and VEGF or a decreased activity or expression of BDNF or an increased activity or expression of VEGF, respectively in the interamacrine, interplexiform amacrine cells, and / or dopamine-secreting ganglion cells.Preferably the ocular disorder is selected from disorders of the posterior segment of the eye.Preferably the ocular disorder is selected from disorders of the vitreous chamber, vitreous membrane, the vitreous body, retina, choroid and optic nerve.Preferably the ocular disorder is a retinal disorder. Preferably the ocular disorder is associated with a decreased dopaminergic activity / dopamine release in the retina. Preferably the ocular disorder would benefit from the increase of dopaminergic activity / release in the retina.Preferably the ocular disorder is selected from age-related and wet macular degeneration, retina dystrophy with photoreceptor loss, hypoxia / anoxia-induced neurodegeneration, retinitis pigmentosa (non-apoptotic type, Newton and Megaw, 2020), toxic retinopathies, premature retinopathy, retinopathies in diabetes mellitus and glaucoma (dopamine-secreting ganglion cell loss type, Liang et al., 2023), ganglion cell damage following optic nerve crash, impaired visual acuity in the elderly age, increased intraocular pressure, myopic choroidal neovascularization, glaucoma. Preferably the ocular disorder is selected from neovascular (wet) age-related macular degeneration, choroidal neovascularization, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy (proliferative and non-proliferative type), retinopathy of prematurity, and further retinal dystrophy with photoreceptor loss, retinitis pigmentosa (non-apoptotic type), hypoxia / anoxia-inducedneurodegeneration, toxic and glaucomatous retinopathies (dopamine secreting-ganglion cell loss type) and age-related impairments in vision acuity.Preferably the ocular disorder is selected from neovascular (wet) age-related macular degeneration, choroidal neovascularization, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy (proliferative and nonproliferative type), retinopathy of prematurity, retinal dystrophy with photoreceptor loss, retinitis pigmentosa (non-apoptotic type), hypoxia / anoxia induced neurodegeneration, toxic and glaucomatous retinopathy (dopamine-secreting ganglion cell loss type) and age-related impairments in vision acuity.Preferably the TAAR 1 agonist compound is used in combination with an anti-VEGF medication, preferably a VEGF signal pathway inhibiting compound, preferably a compound that blocks VEGF or a VEGF receptor, preferably an anti-VEGF antibody, e.g. aflibercept, ranibizumab, bevacizumab.BRIEF DESCRIPTION OF THE FIGURESFigure 1. The chemical structures of the dopaminergic activity enhancer compounds, selegiline and (-)BPAP, and the TAAR1 agonist ulotaront. Other dopaminergic activity enhancer compounds, analogues of (-)BPAP, are (-)PPAP ((-)-l-phenyl-2-propylaminopentane) and (-)IPAP ((-)-l-(indol-3-yl)-2-propylaminopentane).Figure 2. Cytoarchitecture of the retina. Dopamine-containing amacrine cells are located at the inner nuclear layer and dopamine-secreting cells are also located in the ganglion cell layer of the retina. Vertical section of rat retina stained with hematoxylin and eosin. Abbreviations: PHR, photoreceptor layer; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer, OPN, optic nerve fibers. Retinal pigment epithelium (RPE) covers photoreceptor layer.Figure 3. Hypothetical model for regulation of dopamine release evoked by trace amines and dopaminergic activity enhancer compounds from amacrine cells in the retina. Trace amines (phenylethylamine, tyramine, tryptamine etc) are synthesized from amino acids by aromatic amino acid decarboxylase (AADC) in the hypothetical D cells in the retina. Trace amines activate trace amine-associated receptor 1 (TAAR1) and signaling in dopaminergic amacrine cells, which leads to release of dopamine. Dopaminergic activity enhancer compounds (selegiline, (-)BPAP) in specific low concentrations act as exogenous agonists of TAAR1 or TAAR1 agonists(ulotaront) evoke increases in dopamine release [Harsing et al., 2022; 2023], Dopamine released into the extrasynaptic space downregulates AADC activity [Rosetti et al, 1990] and trace amine synthesis in D cells, which then influence TAAR1 activity to negative direction as a feedback inhibition. We assumed that increased dopaminergic neurochemical transmission in retinal amacrine cells restores BDNF / VEGF balance in retinal circuitry and this process has therapeutic benefits in neurodegenerative pathologies of the retina. Light stimulates AADC activity whereas does not influence enhancer compound actions. We also hypothesize that the pathogenesis of retinal neurodegenerative disorders, in which novel vessel formation occurs, is due to an exhaustion of D cells by age and a failure of trace amine production for stimulation of dopamine synthesis at a sufficient rate.Figure 4. Dopaminergic activity enhancer compounds evoke dopamine release from amacrine cells in the retina: a hypothetical mechanism of action. The enhancer compounds (selegiline, (-)BPAP etc) are taken up by dopamine transporter (DAT) into amacrine cells and they activate trace amine-associated receptor 1 (TAAR1). Increased TAAR1 signaling ultimately phosphorylates vesicular proteins involved in exocytosis, upregulates readily releasable pool of dopamine, and increases its vesicular release and storage capacity [Harsing et al., 2022; 2023], Ulotaront may exert similar effects acting as a direct agonist on TAAR1. We assumed that increased dopaminergic neurochemical transmission has therapeutic benefits in neurodegenerative pathologies of the retina via restoring BDNF / VEGF disbalance in retinal circuitry.Figure 5. The time-course of [3H]dopamine release measured from rat retina preparations. Posterior eye cups were prepared, loaded with [3H]dopamine and superfused with aerated and preheated Krebs-bicarbonate buffer. The release of [3H]dopamine was expressed as a fractional rate calculated as per cent of content released in 3 min, i.e. a percentage of the amount of [3H]dopamine in the tissue at the time of the release. [3H]Dopamine release was induced by electrical stimulation (40 V, 20 Hz, 2-msec for 3 min) in fractions 4 (SI) and 18 (S2). The calculated ratio of the electrically stimulated fractional release S2 (2ndstimulation) over fractional release SI (1ststimulation) (S2 / S1) was 0.96+0.09 representing a release of vesicular origin. The calculated ratio of resting fractional release B2 (fraction 17) over fractional release Bl (fraction 3) (B2 / B1) was 0.68+0.05. Tissue [3H]dopamine content was 54.63+8.10 kBq / g at the end of superfusion, mean+S.E.M., n=4. Whenused, drugs were added to the superfusion buffer between the 1stand 2ndelectrical stimulations and maintained throughout the experiment.Figure 6. Concentration-dependent effects of selegiline on electrical stimulation-induced [3H]dopamine release from rat retina preparation. The electrical stimulation-induced [3H]dopamine release was determined as a fractional rate. Selegiline was added to the superfusion buffer from collected fraction 8 in a concentration range from 10'13to 10'5mol / L. Electrical stimulation (40 V, 20 Hz, 2-msec for 3 min) was applied in the 1st(absence of drug, SI) and 2nd(presence of drug, S2) stimulations carried out fractions 4 and 18 and the release was expressed as S2 / S1 ratio. The S2 / S1 value was 0.80+0.05 (n=8) in control experiments (c). One-way ANOVA followed by the Dunnett’s test, F(9,47)=4.131, p=0.006, **p<0.01 vs control, mean+S.E.M., n=3-8 in brackets.Figure 7. Reversal by EPPTB of the enhancer effect of selegiline on [3H]dopamine release from rat retina preparation. The electrical stimulation-induced [3H]dopamine release was determined as a fractional rate. Selegiline was added to isolated retina from fraction 8 in a concentration of 10'9mol / L and maintained throughout the experiment in the presence and absence of EPPTB. When used, EPPTB was added to retina preparation 30 min prior to collection of fraction 1 in a concentration of 10'7mol / L and was maintained throughout the experiment. Student / -statistics for two-means, *p<0.05 vs selegiline treatment, #p<0.05 vs control, mean+S.E.M., n=4-8. Figure 8. Concentration-dependent effects of (-)BPAP on electrical stimulation-induced [3H]dopamine release from rat retina preparation. The electrical stimulation-induced [3H]dopamine release was determined as a fractional rate. (-)BPAP was added to the superfusion buffer from collected fraction 8 in a concentration range from 10'13to 10'5mol / L. Electrical stimulation (40 V, 20 Hz, 2-msec for 3 min) was applied in the 1st(absence of drug, SI) and 2nd(presence of drug, S2), stimulations carried out in fractions 4 and 18 and the release was expressed as S2 / S1 ratio. The S2 / S1 value was 0.89+0.05 (n=8) in control experiments. One-way ANOVA followed by the Dunnett’s test, F(9,43)=43.331, p=0.0036, *p<0.05, **p<0.01 vs control, mean+S.E.M., n=3-8 in brackets.Figure 9. Reversal by EPPTB of the enhancer effect of (-)BPAP on [3H]dopamine release from rat retina preparation. The electrical stimulation-induced [3H]dopamine release was determined as a fractional rate. (-)BPAP was added to isolated retina from fraction 8 in a concentration of 10'11mol / L and maintained throughout the experiment in the presence and absence of EPPTB. When used, EPPTB was added to retina 30min prior to collection of fraction 1 in a concentration of 10'7mol / L and was maintained throughout the experiment. Student / -statistics for two-means, *p<0.05 versus (-)BPAP treatment, #p<0.05 versus control, mean+S.E.M., n=4.Figure 10. Concentration-dependent effects of ulotaront on electrical stimulation-induced [3H]dopamine release from rat retina preparation. The electrical stimulation-induced [3H]dopamine release was determined as a fractional rate. Ulotaront was added to the superfusion buffer from collected fraction 8 in a concentration range from 10'13to 10'5mol / L. Electrical stimulation (40 V, 20 Hz, 2-msec for 3 min) was applied in the 1st(absence of drug, SI) and 2nd(presence of drug, S2), stimulations carried out in fractions 4 and 18 and the release was expressed as S2 / S1 ratio. The S2 / S1 value was 0.81+0.02 (n=9) in control experiments. Note that the concentration-effect curve for ulotaront was bimodal but failed to show biphasic characteristics. One-way ANOVA followed by the Dunnett’s test, F(9,50)=3.161, p=0.0043, *p<0.05, **p<0.01 vs control, mean+S.E.M., n=3-12.Figure 11. Reversal by EPPTB of the TAAR1 agonist ulotaront effect on [3H]dopamine release from rat retina preparation. The electrical stimulation-induced [3H]dopamine release was determined as a fractional rate. Ulotaront was added to isolated retina from fraction 8 in a concentration of 10'9mol / L and maintained throughout the experiment in the presence and absence of EPPTB. When used, EPPTB was added to retina 30 min prior to collection of fraction 1 in a concentration of 10'7mol / L and was maintained throughout the experiment. Student / -statistics for two-means, *p<0.05 vs ulotaront treatment, #p<0.05 versus control, mean+S.E.M., n=6-8.DETAILED DESCRIPTION OF THE INVENTIONIt had been demonstrated earlier that the enhancer compounds increase dopamine release in different brain areas (brain stem, striatum, prefrontal cortex), but their action was restricted to dopaminergic projection neurons only [Miklya, 2002; Harsing et al., 2022], To determine whether or not the releasing effect is also valid for dopaminergic interneurons, retina, in which a series of amacrine cells possess these cellular morphologies, was used (Figure 5). It was found that dopamine enhancer or TAAR1 direct agonist compounds increase dopamine release from the retina acting as exogenous activators of a hitherto unknown hypothetical regulation consisting of the trace amine-producing D cells and dopaminergic amacrine cells expressing TAAR1. The invention isbased upon this finding, which may bear therapeutic importance in neurodegenerative retinal pathologies.Comparing the chemical structures of the enhancer compounds and trace amines, we have speculated that the site of action of the enhancer compounds might be the TAAR1 [Knoll., 2005], Indeed, we were able to prove this concept by using the TAAR1 selective antagonist EPPTB [Bradaia et al., 2009] in enhancer research [Harsing et al., 2022; 2003],Dopaminergic amacrine cells are under the control of trace amines in the retina. Of the known trace amines, we have investigated the effect of phenylethylamine on [3H]dopamine release from rat retina preparation and a marked increasing effect was found on dopamine release (unpublished data). Trace amines diffuse into dopamine-containing amacrine cells and they activate the intracellularly located TAAR1 and its signaling (Figures 3 and 4). This process may induce tonic dopamine release from retinal dopaminergic amacrine cells. Thus, light stimulation increases synthesis and release of dopamine and trace amines in the retina via increasing AADC activity both in amacrine and D cells. Therefore, enhancer compounds and direct TAAR1 agonists may have a similar effect in the retina as the endogenous enhancers.Searching the pathogenesis of retinal disorders led us to focus on two neurobiological factors, the brain-derived neurotrophic factors (BDNF) and vascular endothelial growth factor (VEGF), which are apparently present in the retina in equilibrium in health [Afarid et al., 2020], BDNF in the retina is produced primarily in retinal ganglion cells [Menna et al., 2003], whereas the source of VEGF is the retinal epithelial cells, ganglion cells, Muller glia cells, and also endothelial cells [Penn et al.2008],In neurodegenerative retinal disorders, a disturbed equilibrium of these two neurobiological factors, BDNF and VEGF has been reported [Afarid et al., 2020], BDNF has a role in synaptic connectivity growth and cellular survivals [Seki et al., 2005] and deficiencies of neurotrophins and their receptors are regarded as an aspect of the pathogenesis of neurodegenerative disorders in the retina. VEGF is responsible for development of newly formed vessels in the retina [Liang et al., 2023], Reduced dopamine causes increases in vessel growth by elevating angiogenesis. This disturbed equilibrium of the two neurobiological factors (i.e. decreased levels of BDNF and enhanced VEGF tone) was found in age-related macular degeneration and diabeticretinopathy, two retinal disorders causing blindness in the working population and elderlies more often.Given the potential importance of BDNF and VEGF, two factors present in retinal pathologies, we looked for the regulatory processes involved in their productions. Dopamine increased BDNF expression in cultured mouse striatal cells and the dopamine DI receptor agonist SKF38393 also increased BDNF protein expression levels in rat striatal and hippocampal slices [Kiippers and Beyer, 2001; Williams and Undieh, 2009], The absence of BDNF causes alterations in retina functions [Seki et al., 2005], The levels of BDNF in streptozotocin-treated diabetic rats were found to be reduced, which may lead to apoptosis and neurodegeneration in diabetic retina [Ola et al., 2013],On the other hand, studies are available, which suggest the role of dopamine in the regulation of VEGF production and its signaling by activation of dopamine D2 receptors [Cristina et al., 2005; Sinha et al., 2009], Dopamine D2 receptor agonists were reported to inhibit VEGF secretion in luteinized granulosa cells [Ferrero et al., 2014a, b; 2015], More importantly, Renteria and coworkers

[2020] reported that dopamine D2 receptor activation inhibits VEGF-induced effects in human retina. Assuming that dopamine receptors are involved in regulation of BDNF and VEGF secretion in the retina, these processes may take different locations: DI receptors were identified in other amacrine and bipolar cells in the inner retina, whereas D2 receptors are mostly expressed on rod and cone photoreceptors and horizontal cells in the outer retina [Flood and Eggers, 2021],Based upon the dopaminergic stimulatory control on BDNF and inhibitory control on VEGF secretion, we hypothetize that compounds (i.e. the dopaminergic activity enhancer / TAARl agonist compounds), which increase dopaminergic tone in the retina, restore disturbed equilibrium of the two factors. This restoration can involve increased BDNF and decreased VEGF production and / or release elicited by dopamine or its DI and D2 receptor agonists shifting retinal operation towards the normal direction. The dopaminergic activity enhancer compounds in the low pico / nanomolar concentrations increase depolarization-induced [3H]dopamine release in a phasic mode via activation of TAAR1 and its signaling, this mechanism is shown in Figure 4. [Harsing et al., 2022], Thus, the dopaminergic activity enhancer compounds acting as exogenous agonists on cytoplasmic TAAR1 in dopaminergic amacrine cells maypossess protective effects in neurodegenerative retinal diseases by normalizing the BDNF / VEGF tone:Retina pathologies:decreased retinal dopamineBDNF activity reduced, Activated VEGF and signaling, impaired synaptic connectivity increased novel vessel cellular survivals proliferationDopaminergic activity enhancer / TAARl agonist compounds:increased retinal dopamineBDNF activity increases, Decreased VEGF and signaling, improved synaptic connectivity reduced novel vesseland cellular survivals* proliferation***Enhancers upregulate BDNF expression in retina and mesencephalic slices [Takahata et al., 2003; Hirami et al., 2005]**D2 agonists decrease in VEGF-related processes in the retina [Renteria et al., 2020]Dopaminergic activity enhancer compounds, which are aryl-substituted ethylamine derivatives, possess a neurochemical pattern to increase electrical stimulation-induced [3H]dopamine release without altering resting release from neural tissues [Knoll et al., 1998], Enhancer compounds are also able to evoke exocytosis-mediated [3H]dopamine release from isolated rat retina in an unusually low, pico / nano molar concentration range. This effect of the enhancer compounds is mediated by activation of the trace amine-associated receptor 1 (TAAR1), an intracellularly located G protein-coupled receptor (GPCR) with a hitherto unknown presence in the retina. Enhancer compounds evoked dopamine release with bi-modal characteristics that may have therapeutic importance to protect retina from toxic, high dopamine concentration-evoked overactivation, i.e. impaired vision, mydriasis, and elevated intraocular pressure.The source of [3H]dopamine release in the retina is the dopaminergic amacrine cells, which are, in physiologic conditions, responsible for day-light acuity, regulation of light-adaptive vision, colour perception, contrast sensitivity, and serve as a biological clock [Doyle et al., 2002], In retinal pathology, primarily in age-related macular degeneration and diabetic retinopathy, a decreased brain-derived neurotrophic factor (BDNF) and an increased vascular endothelial growth factor (VEGF) production occur and secretion of both factors is under the control of dopamine levels involving stimulatory dopamine DI and inhibitory dopamine D2 receptors, respectively. The enhancer compound selegiline or (-)BPAP, when they are used in concentrations far below antiapoptotic, scavenger, superoxide dismutase or monoamine oxidase inhibitory concentrations, may normalize retinal BDNF / VEGF disbalance by increasing production of the former and decreasing production of the latter regulatory protein. This goal can be reached by topical administration of dopaminergic enhancer / TAARl agonist compounds (eye drop, ointment or preferably use of insert in conjunctival sac, scleral or intravitreal implant (with biodegradable or non-biodegradable matrix) or intravitreal injection) containing concentration of the most suitable enhancer compound listed, which then is able to penetrate directly into the posterior segment of the eye. During the course of treatment, topical administration will assure the presence of the enhancer / TAARl agonist compounds in required amounts and visual acuity of the patients as well as novel blood vessel formation will be regularly checked in the retina separating responders from non-responders. Topical administration of an enhancer compound or a TAAR1 agonist compound in the dosage forms defined in the description can be used per se or in an add-to-therapy with the currently wildly used intraocular injection of anti -VEGF high molecular weight preparations (i.g. aflibercept, ranibizumab, bevacizumab). Retinal disorders that we target with an enhancer drug or a TAAR1 agonist compound based therapy are those in which inhibitors of VEGF are used and / or in which increased BDNF production may improve synaptic connectivity and cellular survivals: neovascular (wet) age-related macular degeneration, choroidal neovascularization, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy (proliferative and non-proliferative type), retinopathy of prematurity, and further retinal dystrophy with photoreceptor loss, retinitis pigmentosa (non-apoptotic type), hypoxia / anoxa induced neurodegeneration, toxic retinopathies, glaucomatousretinopathies (dopamine-secreting ganglion cell loss type), myopic choroidal neovascularization, and age-related impairments in vision acuity.Compounds according to Formulae I-V, in particular selegiline, (-)BPAP, and ulotaront have been found to show dopaminergic activity enhancer effect in rat retina in vitro. These compounds increased the electrical stimulation-induced [3H]dopamine release when used in 10'12-10'9mol / L concentrations (Figures 6 and 8). The possible source of released dopamine is the dopamine-containing interamacrine and interplexiform amacrine cells, and dopamine-secreting ganglion cells. Selective increases of retinal dopaminergic cell activity (i.e. dopamine release) possess therapeutic importances in neurodegenerative retinal disorders and age-related impairments of vision acuity. These increases in dopamine possibly improve operation of pathologically damaged neuronal circuitry of the retina. Dopaminergic cell activity may be selectively increased in the retina by using medical preparations containing a compound according to Formulae I-V in doses which provide pico-nanomolar concentrations of the active agent within the retina. The therapeutic effect of the compounds according to Formulae I-V in ocular diseases is based on their dopaminergic activity enhancer action.Besides dopaminergic activity enhancer compounds, dopaminergic cell activity may also be selectively increased in the retina by using medical preparations containing a compound acting as a direct agonist on TAAR1, e.g. ulotaront [Heffernan et al., 2022], which provide pico-nanomolar concentrations of the active agent within the retina.Preparation of dopaminergic enhancer compounds is described e.g. in the following patents and patent applications: WO1999007667A1, W01988002254(A1). An abundant teaching can be found on the preparation of low dose medicaments in the following publications: Ahmed and Shah, 2000; Zheng, 2009.Formulation variations of selegiline are well-known in the art [for example Clarke et al., 2003], A new low-dose formulation of selegiline, clinical efficacy, patient preference and selectivity for MAO-B inhibition was reported by Fowler

[2014] , However, formulation of selegiline, other dopaminergic enhancer compounds or ulotaront preferably used here as ophthalmic inserts, implants or intraocular injection has not been reported.The dopaminergic enhancer effect is measurable or detectable among others by the following methods:- by measuring the amount of [3H]dopamine released to electrical stimulation from an isolated mammalian brain, preferably brain stem, preferably rat brain stem or retina preparation, e.g. by the method described in the Examples;- by administration of a candidate dopaminergic enhancer compound in a very broad dose range, wherein a bi-modal, bell-shaped concentration-effect curve is characteristic to the enhancer effect; wherein the lower range shows the “specific enhancer effect” whereas the higher range the “non-specific enhancer effect”.Dopaminergic enhancer compounds primarily influence dopamine release from vesicular stores and exert only a limited or no effect on the non-vesicular (cytoplasmic) release of dopamine. Dopaminergic enhancer compounds increase the electrical stimulation induced release of dopamine when added to a brain derived or retina preparation in a concentration lower than 10'8mol / L, or lower than 10'9mol / L. An “enhancer compound” is a neuronal activity enhancer compound that is capable of exciting in a dose-dependent manner at least a subset of enhancer sensitive neurons, preferably without inhibiting monoamine-oxidase-A (MAO-A), preferably without inhibiting MAO-B.A “dopaminergic enhancer compound” is capable of increasing the electrical stimulation induced release of dopamine when added to a brain derived or retina preparation in a concentration lower than 10'8mol / L, or lower than 10'9mol / L, without affecting the non-vesicular (cytoplasmic) release of dopamine.“Lower” alkyl, alkoxy etc. means preferably Cl -6, Cl -4, Cl -3 or Cl -2 alkyl or -alkoxy etc.As used herein, the term “alkyl” alone or in combinations means a straight or branched-chain hydro-carbon group containing preferably from 1 to 6, preferably 1 to 4 or 1 to 3 carbon atom(s) or 1 to 2 carbon atom(s) (i.e. “Cl-6” “Cl-4” or “Cl-3” or “Cl -2” alkyl groups), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl.The term “C1-C4 alkyl” refers to a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl or n-butyl, iso-butyl or tert-butyl.As used herein, the term "alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy, preferably methoxy. The bond to the parent moiety is through the ether oxygen.The term “C1-C4 alkoxy” refers to a linear or branched alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secbutoxy, or tert-butoxy.As used herein, the term "aryl" refers to a mono- or bicyclic aromatic ring, optionally heterocyclic, e.g.- phenyl, pyridinyl, pyranyl, diazinyl, oxazinyl or dioxinyl,- naphtyl, preferably 1-naphtyl or 2-naphtyl,- indolyl, preferably l-indol-2-yl or 1-indol-yl,- bezodiazolyl, particularly 1,3-benzodiazolyl, preferably l,3-benzodiazol-2-yl, - benzofuranyl, particularly 1 -benzofuranyl, preferably l-benzofuran-2-yl or 1-benzofuran-3-yl; or- benzodi oxolyl, particularly 1,3-benzodioxolyl, preferably l,3-benzodioxol-2-yl. A “heterocyclic” compound or group or ring structure as used herein is a cyclic compound that has, besides carbon atom(s), atoms of at least one non-carbon element(s) as member(s) of its ring(s). Preferably the ring(s) of the heterocyclic compound is / are 5 to 6 membered ring(s).An “alkenyl” as used herein, alone or in combinations, means a straight or branched-chain unsaturated hydrocarbon group containing at least one carbon-carbon double bond, said hydrocarbon group containing preferably from 2 to 6, preferably 2 to 4 or 2 to 3 or 2 carbon atom(s) (i.e. “C2-6”, “C2-4” or “C2-3” or “C2-2” alkyl groups). An “alkynyl” as used herein as used herein, alone or in combinations, means a straight or branched-chain unsaturated hydrocarbon group containing at least one carboncarbon triple bond, said hydrocarbon group containing preferably from 2 to 6, preferably 2 to 4 or 2 to 3 or 2 carbon atom(s) (i.e. “C2-6”, “C2-4” or “C2-3” or “C2-2” alkyl groups).An “alkylcarbonyl” as used herein means an alkyl-CO- group comprising an alkyl and a carbonyl group composed of a carbon atom double-bonded to an oxygen atom, in which the alkyl group is as previously described. The bond to the parent moiety is through the carbon atom of the carbonyl group, ether oxygen.An “arylalkyl” as used herein refers to an aryl alkyl group which is linked to the parent molecule through the alkyl group, which may be further optionally substituted with on or more, preferably one to three or one to two substituents as set forth above. As used herein, the term “fused ring” means that the ring is fused with a group to form a bicyclic group of the formula wherein a single bond between two memberatoms of the rings is, together with said two members, common in, i.e. shared by the two rings.An “alkyl substituent” is not larger, preferably smaller, i.e. shorter, i.e. consists of not more, preferably less chain atoms, preferably carbon atoms, than the group, moiety, e.g. Q, Rl, R2 or R3 which is / are substituted thereby.The term “mono- or di-(Cl-C4 alkyl)amino" refers to an amino group substituted by one or two C1-C4 alkyl groups, such as methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, or isopropylamino.The term “5- or 6-membered aliphatic or aromatic heterocycle containing one or two heteroatoms selected from N, O, and S“ include, for example, pyrrolidinyl, pyrrolidyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thiophenyl, piperidinyl, morpholinyl, piperazinyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl groups.A method is provided for treatment of patients suffering from retinal neurodegenerative disorders using ophthalmic preparations containing dopaminergic activity enhancer / TAARl agonist compounds, their optical enantiomers or racemic mixtures, in therapeutically effective amounts. The invention relates to pharmaceutical preparations, in particular eye drops, solutions, sprays, ointments or powders, preferably insert, implant or intravitreal injection containing the enhancer compounds in hitherto unused low concentrations. The enhancer / TAARl agonist compounds are delivered preferentially into the posterior eye segments, where retina is present, assuring the required concentrations of the biologically active substances in loco. Topically applied enhancer / TAARl agonist compounds may reach the posterior eye segment by penetration though the sclera from the conjunctiva [Koevary, 2003], The pharmaceutical composition may be administered at different intervals, e.g. once daily or b.i.d. as a therapy itself or in combination with anti-VEGF biological compounds.Intravitreal injection or inserts or implant preparations are provided, containing therapeutically effective amounts of enhancer / TAARl agonist compounds to assure the relatively constant concentrations of the compound in the posterior segment of the eye in order to maintain TAAR1 -mediated dopamine release from retinal amacrine cells or ganglion cells-derived dopamine.To improve ophthalmic drug delivery, particularly into the posterior segment of the eye, therapeutic compositions can be prepared as known in the art and disclosed indetail in US Pat. Nos. 2007 / 0020336 Al, EP 3 654 964 Bl, EP 2262 476 Bl, and Kunou et al. 2000; Koevary, 2003; Shastri et al., 2023.Intravitreal injection, insert, implant or other topically applied ophthalmic preparations containing an enhancer / TAARl agonist compound can be used per se or in an add-to therapy with intraocular injection of anti-VEGF high molecular weight preparations (aflibercept, ranibizumab, bevacizumab, etc.). During treatment with an enhancer compound delivered in required amounts, visual acuity of the patients needs to be regularly checked separating patients to responders and non-responders. Other diagnostic procedures, which support to check patients’ conditions during treatment, are preferential hyperacuity perimetry and angiography or fluorescein angiography of the reina.Based upon experiments shown in Examples, ophthalmic preparations as well as inserts to be applied into the conjunctival sac (outpatient use also), scleral or intravitreal implant (with biodegradable and non-biodegradable matrix) or intravitreal injection, containing dopaminergic activity enhancer compounds in 10'12-10'9mol / L concentrations will be applied for treatment of retinal neurodegenerative disorders as sustained release devices.The concentrations of a dopaminergic activity enhancer compound or a direct TAAR1 agonist compound in pharmaceutical preparations were estimated based on the following assumptions:1. Estimated therapeutic concentrations of the enhancer compounds / direct TAAR1 agonists are in the range of 1 O'12- 1 O'9mol / L concentration;2. The dopaminergic activity enhancer compounds / direct TAAR1 agonists distribute in the intracellular compartment of the eye as TAAR1, the potential target of these compounds, is located intracellularly;3. Human eye weights cc 35 g and 60 per cent of which form the total fluid compartment of the organ, i.e. at about 21 ml.The pharmaceutical composition comprising the dopaminergic activity enhancer compound or TAAR1 agonist compound as defined in the specification prepared as an eye drop or other topically applied preparations may contain the compounds in concentrations of 0.01-1000 ng / ml, preferably 0.1-100 ng / ml, estimated volume or weight of an eye drop is 50 pL or 50 pg. This pharmaceutical composition prepared as intravitreal injection may contain the enhancer compounds in concentrations of0.01-1000 ng / ml, preferably 0.1-100 ng / ml solution with an injectable volume of 50 pl.For the treatment of neurodegenerative disorders of the retina, drug delivery is required into the posterior segment of the eye. A bolus intravitreal injection of a compound results in an initial high local concentration followed by a rapid decline in drug concentrations due to drug clearance. Other devices, such as inserts or implants in the eye, may assure a sustained release of enhancer compounds with a relatively constant dopamine release evoked expecting a sustained suppression of VEGF in the retina.EXAMPLESMaterials and MethodsDrugs used[3H]Dopamine (dihydroxyphenylethylamine-3,4[3H], specific activity: 27.8 Ci / mmol), Soluene-350 tissue solubilizer, and Ultima Gold XR liquid scintillation reagent were obtained from PerForm Kft, Budapest, Hungary). The aryl-2-propyl-aminopentane compounds ((-)BPAP HC1) and selegiline HC1 were from Fujimoto Pharmaceutical Co., Osaka, Japan; ulotaront from Biozol, Germany; EPPTB (RO5212773, N-(3-ethoxyphenyl)-4-pyrrolidin-l-yl-3 -trifluoromethylbenzamide) and phenylethylamine from Sigma-Aldrich Chemical Co, Milwaukee, WI, USA were purchased. All other chemicals were of analytical grade.Ethical considerationsAll experimental procedures were approved by local Animal Care Committees and were in accordance with the NIH Guide for the Care and Use of Laboratory Animals, 8th Edition, revised in 2011 and the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research.AnimalsMale Wistar rats weighing 160-180 g were used for investigations and purchased from Toxicoop, Budapest, Hungary. The animals were housed five to a cage in a temperature- and humidity-controlled animal facility on a 12-h light / dark cycle (6.00 a.m. on, 6.00 p.m. off) with food and water available ad libitum. All efforts were done to minimize the harm to animals and the number of animals used.Preparation of rat posterior eye cup lined by the retinaRat posterior eye cup containing the retina was dissected from light-adapted rats [Harsing et al., 2012], Rats were decapitated by a guillotine and the eyeballs were removed from the socket. The eyes were hemisected, the lens and the vitreous body were removed, and the resultant posterior eye cups lined by the retina were immersed in Krebs-bicarbonate buffer (composition in mmol / L: NaCl 118, KC14.7, CaCE 1.25, NaJfcPC 1.2, MgCh 1.2, NaHCOs 25, glucose 11.5, ascorbic acid 0.3, and ISfeEDTA 0.03) at room temperature [Harsing et al., 2012], The Krebs-bicarbonate buffer was aerated with 5% CO2 in oxygen. The experiments were done under laboratory light conditions and consequently, the retinae were light adapted.Release of [3H] dopamine from rat eye cup lined by the retinaRat posterior eye cups were loaded with [3H]dopamine (10 pCi) for 30 min in 1.5 ml aerated (95% 02 / 5% CO2, pH 7.4) and preheated (37 °C) Krebs-bicarbonate buffer [Harsing et al., 1992], After loading the tissues with [3H]dopamine, the posterior eye cups were transferred into low volume (0.3 ml) superfusion chambers (Experimetria Kft, Budapest, Hungary) and superfused with aerated and preheated Krebs-bicarbonate buffer. The flow rate was kept at 1 ml / min by a Gilson multichannel peristaltic pump (type M312, Villiers-Le Bel, France). The superfusate was discarded for the first 60 min period of the experiments, then twenty -five 3 -min fractions were collected by a Gilson multichannel fraction collector (type FC-203B, Middletown, WI, USA). When used, biphasic electrical field stimuli (40 V voltage, 20 Hz frequency, 2-msec impulse duration for 3 min in fractions 4 and 18) were delivered by Grass S88 Electrostimulators (Quincy, MA, USA) to facilitate [3H]dopamine release. Drugs were added from collected fraction 8 to retina preparation and maintained throughout the experiments.Determination of [3H]dopamine effluxAt the end of superfusion, tissues were collected from the superfusion chambers, weighed, and solubilized in 0.4 ml Soluene-350. An aliquot (50 pl) was mixed with 5 ml of liquid scintillation reagent (Ultra Gold XR) and subjected to liquid scintillation spectrometry for determination of tissue content of radioactivity. The tissue content of [3H]dopamine was expressed as kBq / g tissue.To determine the radioactivity released from retina preparation, a sample (1 ml) of the superfusate was mixed with 5 ml of liquid scintillation reagent and subjected to liquid scintillation spectrometry. The efflux of [3H]dopamine was expressed in kBq / g / 3 min fraction or as a fractional rate, i.e. a percentage of the amount of radioactivity in thetissue at the time of the release was determined. To estimate the electrically induced [3H]dopamine overflow, the mean of the basal outflow determined before and after stimulation was subtracted from each sample and summed [Harsing et al., 1992], The effects of drugs on resting [3H]dopamine release were determined in the presence and absence of drugs and was expressed by the ratio of [3H]dopamine efflux in fraction 17 (presences of drugs, B2) and fraction 3 (absence of drug, Bl) i.e. B2 / B1 ratio. The effects of drugs on electrical stimulated [3H]dopamine release were determined in the presence and absence of drugs and was expressed by the ratio of the stimulated [3H]dopamine release in response to the 2nd (presence of drug, S2) and 1st (absence of drug, SI) stimulations, i.e. S2 / S1 ratio (Figure 5). The Quattro Pro and the GraphPad Prism computer programs were used for data calculation.Statistical analysesThe Student / -statistics for two-means and the one-way ANOVA followed by the Dunnett’s test were used for statistical analysis of the data as appropriate. The mean±S.E.M. was calculated and the number of independent determinations was indicated with n. A level of probability (p) less than 5% was considered significant.Results1. Release of [3H]dopamine from rat retinaAfter a 60-min initial washout period, posterior eye cups tissue content of [3H]dopamine reached a value of 84.69±11.67 kBq / g and this content of radioactivity declined to 54.63±8.10 kBq / g during the following 75 min superfusion period (mean±S.E.M. n=4). These data indicate that approximatively 40 per cent of tissue content of [3H]dopamine is released during the course of the experiment.The resting [3H]dopamine release approached a rate of 2.62±0.52 per cent of total tissue content of radioactivity in 3 min determined after the 60-min initial washout period. When the superfused posterior eye cups were stimulated electrically, the release of [3H]dopamine increased from 1.71±0.21 kBq / g / 3 min to 2.70±0.30 kBq / g / 3 min (2.22±0.24 and 3.60±0.25 per cent of tissue [3H]dopamine content released in 3 min, respectively, n=4, p<0.01) (Figure 5). [3H]Dopamine release induced by electrical stimulation is an external Ca2+-dependent process, originates from vesicles, and the release is a result of exocytosis [Harsing, 2008],2. Effects of the dopaminergic activity enhancer drug selegiline on [3H]dopamine release from rat retina preparationsTo investigate whether selegiline possesses dopaminergic activity enhancer effect, the drug was added to rat retina preparations in increasing concentrations (concentration range: 10'13to 10'5mol / L). Figure 6 shows that selegiline increased electrical stimulation-induced [3H]dopamine release in concentrations of IO'10and 10'9mol / 1, whereas this release was decreased at higher concentrations. The effect was considered as specific enhancer effect.The dopaminergic enhancer activity of selegiline exhibited a bi-modal characteristic on [3H]dopamine release from rat retina preparation. The rising phase of the release curve can be explained by activation of TAAR1 and increase the size of the readily releasable dopamine pool. The declining phase in the concentration-effect curve occurred when the applied concentrations of selegiline were elevated towards the non-selective enhancer range. TAAR1 heterodimerization with other receptors (possibly presynaptic dopamine D2 receptors) can be involved in the declining phase as receptor heterodimerizations may swich off receptor functions [Harsing et al., 2025], While selegiline enhanced electrical stimulation-induced [3H]dopamine release in pico / nano-molar concentrations, it was without effect on resting [3H]dopamine release in this concentration range (Table 1). This finding indicates that selegiline primarily alters dopamine release originated from vesicular stores, and it exerts only marginal effect on external Ca2+-independent resting release; these are characteristics for the enhancer compounds.Table 1. Effects of the enhancer compounds selegiline and (-)BPAP and the TAAR1 agonist compound ulotaront on resting electrical stimulation-induced [3H]dopamine release from rat posterior eye cup (retina) preparationEnhancer / Concentration [3H]Dopamine release TAAR1 drugs (mol / L) electrically induced resting (S2 / S1) (B2 / B1)1. Control - 0.80±0.05 0.76±0.07 2. Selegiline IO'101.28±0.09** 0.64±0.05 3. Selegiline IO'91.31±0.06** 0.63±0.031. Control - 0.89±0.05 0.70±0.03 2. (-)BPAP IO'121.42±0.18* 0.80±0.133. (-)BPAP IO'111.36±0.11* 0.58±0.041. Control 0.81±0.04 0.78±0.04 2. Ulotaront 10-i° 1.15±0.03* 0.52±0.03* 3. Ulotaront IO'91.26±0.01* 0.63±0.02*Posterior eye cups were prepared, loaded with [3H]dopamine and superfused with aerated and preheated Krebs-bicarbonate buffer. The release of [3H]dopamine was expressed as a fractional rate. Stimulated [3H]dopamine release was induced by electrical stimulation (40 V, 20 Hz, 2-msec for 3 min) in fractions 4 (SI) and 18 (S2) and the S2 / S1 ratio was calculated. The resting [3H]dopamine release was expressed by the ratio of fractional release B2 (fraction 17) over fractional release Bl (fraction 3). When used, drugs were added to the superfusion buffer between the 1stand 2ndelectrical stimulations and maintained throughout the experiment. For selegiline: S2 / S1: One-way ANOVA followed by the Dunnett’s test, F(2,21)=9.601, p=0.001, **p<0.01 vs control. B2 / B1: One-way ANOVA followed by the Dunnett’s test, F(2, 21)= 1.746, p=0.198, mean±S.E.M., n=8. For (-)BPAP: S2 / S1: One-way ANOVA followed by the Dunnett’s test, F(2,21)=4.946, p=0.017, *p<0.05 vs control. B2 / B1: One-way ANOVA followed by the Dunnett’s test, F(2,21)=1.977, p=0.163, mean±S.E.M., n=8. For ulotaront: S2 / S1: One-way ANOVA followed by the Dunnett’s test, F(2.9)=10.70, p=0.004, *p<0.05 vs control. B2 / B1: One-way ANOVA followed by the Dunnett’s test, F(2.9)=13.890, p=0.001, *p<0.05 vs control. mean±S.E.M., n=4.3. The TAAR1 antagonist EPPTB suspends the enhancer effect of selegiline on [3H]dopamine release in rat retina preparationIt has been reported previously that EPPTB, the first described selective inhibitor of TAAR1 [Bradaia et al., 2009], did not influence resting or electrical stimulation-induced [3H]dopamine release in rat striatum when added per se in 10'8or 10'7mol / L concentration [Harsing et al., 2022], This finding suggests that TAAR1 does not exhibit constitutive activity in dopaminergic neurochemical transmission in our experimental conditions.As shown in Figure 7, EPPTB suspended the dopaminergic enhancer effect of selegiline on electrical stimulation-induced [3H]dopamine release in rat retina preparation. Weconcluded from this observation that the dopaminergic enhancer activity may be due to an agonist-induced activation of TAAR1.4. Effects of the dopaminergic activity enhancer drug (-)BPAP on [3H] dopamine release from rat retina preparations(-)BPAP increased the electrical stimulation-induced [3H]dopamine release from rat retina preparation when added in a concentration range of 10'13to 10'5mol / L (Figure 8). Similarly to selegiline, this effect of (-)BPAP was biphasic: it increased electrical stimulation-induced release of [3H]dopamine in concentrations of 10'12and 10'11mol / L and 10'6and 10'5mol / L, respectively. The former effect was considered as a specific dopaminergic activity enhancer effect, whereas that appeared in high concentrations of (-)BPAP was probably due to a monoamine oxidase type A (MAO-A) enzyme inhibition [Harsing et al., 2022],Moreover, the dopaminergic activity enhancer effect of (-)BPAP exhibited a bi-modal effect: it increased electrical stimulation-induced release of [3H]dopamine in concentrations of 10'12and 10'11mol / L and this effect was reduced in concentration of IO'10mol / L and above. This phenomenon showed great similarities to the action of selegiline (Figure 6). Although we explain the rising phase of the concentration-effect curves by increases in readily releasable neurotransmitter pool size, TAAR1 and probably dopamine D2 receptor heterodimerization can be involved in the declining phase. We have concluded previously that TAAR1-D2 receptor heterodimerization may result in a reduced functional activity of TAAR1 [Harsing et al., 2025], The decline in the concentration-effect curves occurred when the applied concentrations of (-)BPAP were elevated towards the non-selective enhancer range.Our experiments also indicate that (-)BPAP applied in enhancer concentrations was without effect on resting [3H]dopamine release (Table 1). This finding suggests that (-)BPAP primarily alters dopamine release originated from vesicular stores and it exerts only marginal effect on non-vesicular dopamine release. Similar effects were observed for the dopaminergic enhancer compound selegiline as well.5. Effect of EPPTB on (ffEPAP -induced [3H]dopamine release from rat retinaAn interaction study was made to determine whether EPPTB influences the enhancer effect of (-)BPAP on retinal [3H]dopamine release. EPPTB added in a concentration of 1 O'7mol / L suspended the stimulatory effect of (-)BPAP on electrical stimulation-induced [3H]dopamine release evoked in 10'11mol / L concentration from rat retina preparation (Figure 9). This finding indicates that the enhancer compound (-)BPAP and the TAAR1antagonist EPPTB interact and (-)BPAP may bind to and stimulate TAAR1 in dopaminergic amacrine cells and consequently the release as well. EPPTB by itself was without effect on electrical-stimulation-induced [3H]dopamine release (Figure 9).6. Effects of the TAAR1 agonist ulotaront on [3H]dopamine release from rat retina preparationsThe TAAR1 agonist ulotaront increased the electrical stimulation-induced [3H]dopamine release from rat retina preparation when added in a concentration range of 10'13to 10'5mol / L (Figure 10). Similarly to the dopaminergic activity enhancer compounds, ulotaront increased the electrical stimulation-induced [3H]dopamine release from retina preparation when added in concentrations of IO'10and 10'9mol / L. This effect was considered as a direct agonist effect on TAAR1. In contrast to enhancer drugs, ulotaront failed to evoke increase of [3H]dopamine release when added in high conentrations (10‘6and 10'5mol / L) indicating that this compound does not exert inhibitory effect on MAO activity.7. Effect of EPPTB on ulotaront-induced [3H]dopamine release from rat retina EPPTB added in a concentration of 10'7mol / L suspended the stimulatory effect of ulotaront on electrical stimulation-induced [3H]dopamine release evoked in 10'9mol / L concentration from rat retina preparation (Figure 11). 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Claims

CLAIMS1. A TAAR1 agonist compound for use in the treatment or prevention of an ocular disorder associated with a decreased dopaminergic activity or decreased dopamine release in the eye.

2. The TAAR1 agonist compound for use according to claim 1, wherein the TAAR1 agonist compound is administered topically.

3. The TAAR1 agonist compound for use according to claim 1 or 2, wherein the ocular disorder is a retinal disorder.

4. The TAAR1 agonist compound for use according to any one of claims 1-3, wherein the TAAR agonist compound is a compound of Formula (I)whereinR1and R2are each independently hydrogen or C1-C4 alkyl,R3and R4are each independently hydrogen or C1-C4 alkyl,R5and R6are each independently hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, mono-or di-(Ci-C4 alkyl)amino, phenyl, or 5- or 6-membered aliphatic or aromatic heterocycle containing 1 or 2 heteroatoms selected from N, O, S,or pharmaceutically acceptable salt or stereoisomer thereof.

5. The TAAR1 agonist compound for use according to claim 4, wherein the TAAR agonist compound is a compound of Formula (la)whereinR1and R2are each independently hydrogen or C1-C4 alkyl,R3and R4are each independently hydrogen or C1-C4 alkyl,R5and R6are each independently hydrogen, halo, or C1-C4 alkyl,or pharmaceutically acceptable salt thereof.

6. The TAAR 1 agonist compound for use according to claim 4, wherein the TAAR agonist compound is ulotaront.

7. The TAAR1 agonist compound for use according to any one of claims 1-3, wherein the TAAR agonist compound is a compound of Formula (II),whereinQ is a group consisting of a substituted or unsubstituted, aromatic, six-membered ring which may or may not have one or two heteroatoms,orQ is a substituted or unsubstituted bicyclic group which consists ofa benzene ring and, fused to said benzene ring,a saturated or unsaturated five- or six-membered ring which may or may not have one to three, preferably one to two heteroatom(s)wherein if Q is substituted,said substituent is selected from the group consisting of hydrogen, hydroxyl, Cl -4 alkyl, Cl -4 alkoxy and halogen, preferably Q is substituted with one or two substituent(s) or is unsubstituted,Ri is Cl -5 alkyl, preferably Cl -4 alkyl, preferably methyl, ethyl or propyl;R-2 is hydrogen, Cl -4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 alkylcarbonyl, C6-10 aryl or C7-11 arylalkyl;R3 is hydrogen, methyl or ethyl,or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The TAAR1 agonist compound for use according to claim 7, whereinQ is phenyl,Ri is methyl, ethyl or propyl,R2 is C2-3 alkyl, C2-3 alkenyl or C2-3 alkynyl,R3 is hydrogen or methyl.

9. The TAAR1 agonist compound for use according to claim 8, wherein the compound is A-methyl-l-phenyl-N-prop-2-ynylpropan-2-amine (deprenyl).

10. The TAAR1 agonist compound for use according to claim 7, wherein the compound is a compound according to Formula (IV)wherein Ri is a C2-4 alkyl, preferably ethyl or propyl;R2 is hydrogen, Cl-3 alkyl, C2-3 alkylcarbonyl or C6-10 aryl;R3 is hydrogen, methyl or ethyl, preferably hydrogen,or pharmaceutically acceptable salt or stereoisomer thereof.

11. The TAAR1 agonist compound for use according to claim 9, wherein the compound is benzofuranylpropylaminopentane (BPAP).

12. The TAAR1 agonist compound for use according to any one of the preceding claims, wherein the compound is administered in a dose of 0.01-1000 ng / ml.

13. The TAAR1 agonist compound for use according to any one of the preceding claims, wherein the compound is administered in a dose providing a concentration of the compound in the eye of 1 O'12- 1 O'8mol / L.

14. The TAAR1 agonist compound for use according to any one of the preceding claims, wherein the compound is administered in a dose providing a concentration of the compound in the retina of 1 O'12- 1 O'8mol / L.

15. The TAAR1 agonist compound for use according to claim 9, wherein the compound is administered topically to the eye in a dose providing a concentration of the compound of 10'10-10'9mol / L in the retina.

16. The TAAR1 agonist compound for use according to claim 11, wherein the compound is administered topically to the eye in a dose providing a concentration of the compound of 10'12-10'umol / L in the retina.

17. The TAAR1 agonist compound for use according to any one of the preceding claims, wherein the compound is formulated as an eye drop, ocular insert, ocular implant or intravitreal injection.

18. The TAAR1 agonist compound for use according to any one of the preceding claims wherein the ocular disease is selected from age-related and wet neovascular macular degeneration, choroidal neovascularization, macular edema following retinal vein occlusion, retina dystrophy with photoreceptor loss, hypoxia / anoxia-induced neurodegeneration, retinitis pigmentosa non-apoptotic type, toxic retinopathies, retinopathy of prematurity, diabetic macular edema, diabetic retinopathy proliferative and non-proliferative types in diabetes mellitus, retinal ganglion cell damage following optic nerve crash, glaucomatous retinopathies dopamine-secreting ganglion cell loss type, impaired visual acuity in the elderly age, increased intraocular pressure, myopic choroidal neovascularization.

19. The TAAR1 agonist compound for use according to any one of the preceding claims wherein the TAAR1 agonist compound is used in combination with an anti-VEGF compound.

20. A pharmaceutical composition comprising a TAAR1 agonist compound and at least one pharmaceutically acceptable carrier or excipient, wherein the pharmaceutical composition is for intraocular administration.

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