Combinations for use in restoring cognitive and behavioural deficits and improving memory deficits in individuals born preterm

Abstract

The present invention relates to a pharmaceutical combination comprising a positive allosteric modulator ( PAM) of the α5 subunit of the extra-synaptic GABAA receptor and a positive allosteric modulator of the δ subunit of the extra-synaptic GABAA receptor for use in restoring behavioural deficits and improving memory deficits in individuals born preterm.

Description

[0001] "COMBINATIONS FOR USE IN RESTORING COGNITIVE AND

[0002] BEHAVIOURAL DEFICITS AND IMPROVING MEMORY DEFICITS IN

[0003] INDIVIDUALS BORN PRETERM"

[0004] Cross-Reference to Related Applications

[0005] This Patent Application claims priority from Italian Patent Application No. 102024000001089 filed on January 22, 2024, the entire disclosure of which is incorporated herein by reference.

[0006] Technical field

[0007] The present invention relates to combinations for use in restoring cognitive and behavioural deficits and improving memory deficits in individuals born preterm.

[0008] Background of the invention

[0009] 1-5% of all babies are born severely preterm. Over the last three decades, major therapeutic advances in neonatal care units have exponentially increased the survival rate of preterm infants at an increasingly early age, drastically reducing the occurrence of severe brain injury and associated neurological deficits (both motor and cognitive) in this population.

[0010] However, nowadays, preterm infants are still at high risk of developing more subtle neuropsychological deficits (involving visual-spatial skills, working memory and cognitive performance) and major behavioural problems, including social defects and maladaptive behaviour.

[0011] In fact, an increase in the incidence of diagnosed neuropsychiatric diseases (25-50% of preterm infants born at <32 weeks' gestational age) in the preterm population has been observed in recent decades. Decades of research in the past have investigated the health problems associated with prematurity due to birth complications such as hypoxia and cerebral blood flow instability as a primary cause of severe brain injury associated with very serious neurological sequelae. It has recently been hypothesised that inflammation and oxidative stress may be the reason for milder deficits in brain development, such as psychological and behavioural deficits in preterm infants.

[0012] However, these lines of research did not focus on the intrinsic biology of prematurity and were conceived on the basis of the health needs of preterm infants born 30 years ago, most of whom had brain injuries. To date, there are still very few studies that have investigated further mechanisms underlying the brain microstructural abnormalities associated with the significant behavioural deficits that characterise individuals born preterm who are currently born in increasingly early foetal stages and who, to date, do not experience serious complications as a result of preterm birth and mostly survive without brain injury.

[0013] These possible intrinsic mechanisms related to the biology of prematurity include loss of key placental factors important for foetal development during the last trimester of pregnancy.

[0014] Premature infants, for example, do not receive placental insulin-like growth factor-1 (IGF-1), an important foetal growth hormone in utero, which plays a key role in promoting the growth and differentiation of several cell types, including brain cells.

[0015] As a result, premature infants have drastically lower serum levels of IGF-1 than foetuses of corresponding age while still in utero. Low postnatal IGF-1 levels are associated with several serious complications of prematurity, including retinopathy of prematurity, bronchopulmonary dysplasia and neurodevelopmental problems at two years of age.

[0016] However, there are still no approved drug therapies for the treatment of cognitive and behavioural deficits in individuals born preterm.

[0017] Contents

[0018] The aim of the present invention is therefore to provide a new treatment for cognitive and behavioural deficits in individuals born preterm.

[0019] This purpose is achieved by a pharmaceutical combination comprising a positive allosteric modulator (PAM) of the a5 subunit of the extra-synaptic GABAA receptor or a pharmaceutically acceptable salt thereof and a positive allosteric modulator of the 5 subunit of the extra-synaptic GABAA receptor for use in restoring cognitive and behavioural deficits and improving memory deficits in individuals born preterm according to claim 1.

[0020] Brief description of the drawings

[0021] The present invention will now be described in detail with reference to the figures of the accompanying drawings, wherein:

[0022] Figure la illustrates, on the left, the quantification of myelinated axon density in PT mice. The bars represent the mean ± SEM. Two-tailed Student's t-test,

[0023] **p < 0.01; on the right, quantification of the mean ± SEM of the ratio G. Two-tailed Student's t-test, **p < 0.01.;

[0024] Figure lb illustrates the quantification of PV and SST interneuron density in CAI and mPFC brain slices of PT mice. The bars represent the average density of PV or SST positive cells of all the animals analysed ± SEM. Student's two-tailed t-test, *p < 0.05, **p < 0.01;

[0025] Figure 1c illustrates the high / low frequency (H / L) ratio in EEG experiments in PT mice. The bars represent the average H / L ratio for all registered animals ± SEM. Mann- Whitney test, *p < 0.05.

[0026] Figure Id illustrates, on the left, the quantification of the mean ± SEM of the grooming time in the self-grooming test of PT mice. Mann-Whitney test, *p < 0.05; in the centre, the quantification of the mean ± SEM of the sociability index in the three-chamber test. Two-tailed Student's t-test, **p < 0.01; on the right, the quantification of the mean ± SEM of the discrimination index in the OL test. Two-tailed Student's t-test, *p < 0.05.

[0027] Figure 2a shows, on the left, the stimulusresponse curves depicting the average number of action potentials (± SEM) elicited by injections of increasing depolarising currents on pyramidal neurons in the CAI region of acute hippocampal slices from PT mice and for each recorded cell (from 8 CTRL mice, 9 JBl-treated mice, 5 litters). Two-way ANOVA RM, p <0.01, Sidak's post hoc multiple comparison test, *p<0.05, **p<0.01; on the right, the quantification of rheobase. The bars represent the mean ± SEM for each recorded cell (from 8 CTRL mice, 9 JBl-treated mice, 5 litters). Student's two-tailed t-test, *p < 0.05.

[0028] Figure 2b illustrates the quantification of the amplitude of bicuculline-induced tonic currents in neurons of PT mice. The bars represent the mean ± SEM, for each recorded cell (from 11 CTRL and 11 JBl-treated mice, 4 litters). Mann-Whitney test, *p < 0.05. Figure 3a illustrates the quantification of the mean ± SEM of the time spent performing the defined grooming behaviour (self-hygiene) in control and PT mice treated as adolescents with GL-II-73 or carrier. Two-way ANOVA, p < 0.01, Tukey's post hoc multiple comparison test, *p < 0.05, ** p < 0.01.

[0029] Figure 3b shows the quantification of the mean ± SEM of the discrimination index in the OL test in control (CTRL) and PT mice treated as adolescents with GL-II-73 or carrier. Two-way ANOVA, p < 0.05, Tukey's post hoc multiple comparison test, **** p < 0.0001.

[0030] Figure 3c shows the quantification of the mean ± SEM of the discrimination index in the OL test in control (CTRL) and PT mice treated as adolescents with GL-II-73 + Ganaxolone (GNX) or carrier. Two-way ANOVA, p < 0.0001, Tukey's post hoc multiple comparison test, * p < 0.05, **** p < 0.0001.

[0031] Description of embodiments

[0032] To overcome the shortage of preclinical models that recapitulate the physiological and behavioural deficits that characterise individuals born preterm today, the inventors recently developed a new mouse model by transiently inhibiting IGF-1 signalling during the period in mice corresponding to the third trimester of pregnancy in humans. This new mouse model (henceforth referred to as the preterm model (PT mice)) exhibits microstructural, functional and behavioural changes in the brain that resemble brain disorders typical of infants born preterm nowadays. In particular, the PT model shows reduced myelination of the white matter, a reduced number of interneurons and a lower ratio between powers in the high-frequency and low-frequency bands in EEG recordings (indicating higher relative power in the low-frequency bands and lower power in the high-frequency bands) compared to controls, as observed in preterm infants.

[0033] In addition, PT mice displayed maladaptive behaviours, including social impairment and repetitive behaviour, as well as memory impairments, which are similar to what was observed in a cohort of severely to moderately preterm infants (born before 32 weeks' gestation) carefully selected because they were free from any kind of brain injury at birth.

[0034] However, although the mouse model was designed to address the need to find a model for the new population of premature individuals without brain injury, it is also inclusive (at least in part) of the population of premature infants with brain injury.

[0035] These data strongly validate the PT mouse as a valid preclinical model to study the mechanism underlying the behavioural alterations of prematurity and to test therapeutic strategies.

[0036] Therefore, by exploiting the PT mouse model, the possible mechanism underlying the cognitive / behavioural deficits that characterise individuals born preterm was studied.

[0037] To begin the investigation of possible cellular mechanisms underlying behavioural phenotypes in PT mice, the intrinsic excitability of hippocampal pyramidal neurons (an important brain region involved in behavioural and cognitive functions) was assessed by performing patch-clamp recordings on pyramidal cells in the CAI region of acute hippocampal slices taken from adolescent mice. Interestingly, pyramidal neurons of PT mice emitted a higher number of action potentials in response to gradual phases of depolarising current than those of controls, indicating increased excitability .

[0038] The increase in intrinsic excitability of PT mice was not due to alterations in passive properties (e.g. input resistance) or active properties (e.g. action potential threshold), which were similar between PT mice and controls. Results on the reduction in the number of interneurons (neurons responsible for inhibitory GABAergic transmission) in PT mice suggested investigating the deficiency of neuronal inhibitory (GABAergic) tone as a possible mechanism underlying the increased excitability of CAI pyramidal neurons (as assessed by AP recordings).

[0039] Therefore, since GABA plays a key role in the control of neuronal excitability through tonic inhibition - exerted by the activation of extrasynaptic GABAA receptors (which differ from synaptic GABAARS due to the presence of the a5 and 5 subunits), tonic GABAergic currents were studied in PT mice and control mice.

[0040] Electrophysiological measurements of GABAergic tonic inhibition were performed in acute brain slices of adolescent mice. In particular, it was found that the neurons of adolescent PT mice displayed a lower tonic current than controls. This result is in agreement with the increased excitability observed in hippocampal pyramidal neurons of PT mice.

[0041] According to the present invention, a pharmaceutical combination is provided, comprising a positive allosteric modulator (PAM) of the a5 subunit of the extra-synaptic GABAA receptor and a positive allosteric modulator of the 5 subunit of the extra-synaptic GABAA receptor for use in restoring cognitive and behavioural deficits and improving memory deficits in individuals born preterm.

[0042] The term "combination" refers to the separate administration of a formulation comprising a positive allosteric modulator (PAM) of the a5 subunit of the extra- synaptic GABAA receptor and a formulation comprising a positive allosteric modulator of the 5 subunit of the extra- synaptic GABAA receptor that can be administered simultaneously, separately or sequentially, but also to the administration of a single formulation containing both modulators .

[0043] A "positive allosteric modulator (PAM) of the a5 subunit of the extra-synaptic GABAA receptor" (Q5-GABAAR PAM) refers to a compound capable of activating the extra-synaptic GABAA receptor leading to the opening of the ion channel and the selective passage of chlorine through its pore. In this context, the term modulator also includes a compound that increases the function of the receptor in the presence of its natural ligand, y-aminobutyric acid.

[0044] In particular, the positive allosteric modulator (PAM) of the a5 subunit of the extra-synaptic GABAA receptor is selected from the group consisting of the ethyl ester of (R)-8-ethynyl-6- (2-fluorophenyl)-4-methyl-4H-2,5,10b- triaza-benzo [e]azulene-3-carboxylic acid (SH-053-R-CH3-

[0045] 2'F), 3- (2,5-difluorophenyl)-7- (1,1-dimethylethyl)-6-[(1- methyl-lH-1,2,4-triazol-5-yl)metoxy] -1,2,4-triazole[4,3- b]pyridazine (L-838,417), 6,6-dimethyl-3- (3- hydroxypropyl)thio-1- (thiazol-2-yl)-6,7-dihydro-2- benzothiophene-4 (5H)-one, NS11821 or pharmaceutically acceptable salts thereof and compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0046] (I) wherein:

[0047] X is selected from the group consisting of N, CH, C- F, C-Cl, C-Br, C-I and C-NO2;

[0048] Ri is selected from the group consisting of Br, -C=CH, and cyclopropyl; Rs is selected from the group consisting of H, CH3, CH2-CH3, CH(CH3)2, OH, F, Cl, CF3and CC13; and

[0049] Rio and RH are independently selected in the group consisting of H, C1-6 alkyl, cycloalkyl or taken together with nitrogen form a heterocycloalkyl ring with 3-6 members.

[0050] In an embodiment, X is selected from the group consisting of N, CH and C-F.

[0051] In an embodiment, Ri is -C=CH.

[0052] In an embodiment R3 is selected from the group consisting of H and CH3.

[0053] In an embodiment, Rio and RH are independently selected from the group consisting of H and Cl-6 alkyl.

[0054] In an embodiment the «5-GABAAR PAM is selected from the group consisting of:

[0055]

[0056] Preferably the compound of formula (I) is GL-II-73.

[0057] Importantly, treatment with an «5-GABAAR PAM, e.g. GL- II-73, by enhancing tonic inhibition, is able to significantly restore behavioural deficits (grooming task) and improve memory deficits (object localisation test) in PT mice.

[0058] Treatment involves the administration, in combination with the «5-GABAAR PAM, of a positive allosteric modulator of the 5 subunit of the extra-synaptic GABAA receptor (5- GABAAR PAM). In an embodiment the positive allosteric modulator of the 5-subunit of the extra-synaptic GABAA receptor is selected from the group consisting of ganaxolone, gabaxadol, zuranolone, 1- ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy- 3,13-dimethylhexadecahydro-lH-cyclopenta [a]phenanthren-17- yl)-2- (2H-1,2,3-triazol-2-yl)ethan-l-one (SGE-516), 1-

[0059] [ (3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3- (methoxymethyl)- 13-methyl-2,4,5,6,7,8,9,10,11,12,14,15,16,17- tetradecahydro-lH-cyclopenta [a]phenanthren-17-yl]-2- (5- methyltetrazol-2-yl)ethanone (Sage-324), allopregnanolone, brexanolone, LYT-300 or pharmaceutically acceptable salts thereof.

[0060] In an embodiment the positive allosteric modulator of the 5 subunit of the extra-synaptic GABAA receptor is ganaxolone .

[0061] Advantageously, this association enhances the effect in memory performance observed with «5-GABAAR PAM treatment alone. In particular, treatment with the PAM «5-GABAAR in combination with a PAM 5-GABAAR is able to significantly restore memory (object localisation test).

[0062] Further characteristics of the present invention will become apparent from the following description of some merely illustrative and non-limiting examples.

[0063] Examples EXAMPLE 1 Validation of the mouse model of prematurity In order to validate the mouse model of prematurity, a number of morphological, functional and behavioural characteristics that, according to the literature, were known to be impaired in children and adolescents born prematurely were assessed. la) PT mice show reduced myelinisation of white matter, similar to that reported in children and adolescents born preterm (Fig, la).

[0064] To assess myelinisation, at postnatal day P45 control (CTRL) and PT mice were sacrificed and the brains fixed in a solution consisting of glutaraldehyde (2%) and paraformaldehyde (2%) for electron microscopy analysis. After several steps in osmium-based solutions (1%) dehydrated with increasing concentrations of alcohol solutions (70%-90%-96%-100%), 70 nanometre sections containing the corpus callosum were acquired under a transmission-based electron microscope. The maximum and minimum axon lengths and widths, as well as the maximum and minimum myelin widths, were calculated for each myelinated axon, for the calculation of the ratio G, universally used as an index of myelinisation.

[0065] A marked decrease in the density of myelinated axons and a thinning of the myelin sheath of the axons (quantified by G-ratio analysis; G-ratio = inner axon diameter / total axon diameter with myelin) was found, with no difference in the calibre of the axon diameter in the axons of PT mice. lb) PT mice displayed a reduction in the number of interneurons, similar to that reported in babies born preterm (Fig. lb).

[0066] To assess the number of interneurons, at postnatal day P45 CTRL and PT mice were sacrificed and the brains fixed in a (4%) paraformaldehyde compound solution for confocal microscopy analysis. Specifically, after post-fixation with paraformaldehyde (4%) and cryopreservation with solutions containing sucrose (30%), 40 micrometre microtome slices were prepared, containing hippocampus or prefrontal cortex. After staining with parvalbumin-specific antibodies or with a genetic reporter containing td-tomato in SST+ / Td-tomato+ mice confocal images containing the entire thickness of the slice (z stack: 20, 2 micrometres) of the hippocampus or prefrontal cortex were acquired. All the marked cells were counted and normalised to the area or volume of the section.

[0067] The number of interneurons in the CAI subregion of the hippocampus and in the prelimbic subregion (PrL) of the medial prefrontal cortex (mPFC) was assessed by performing immunohistochemistry on brain slices from PT mice. It was found that PT mice displayed a reduced number of interneurons (both parvalbumin-positive (PV+) and somatostatin-positive (SST+)) in the hippocampal and cortical areas analysed.

[0068] 1c) PT mice displayed an electroencephalogram (EEG) similar to that reported in young adults born preterm (Fig. Ic).

[0069] In order to evaluate EEG waves, frontoparietal EEG was recorded in awake mice with their head attached via a stereotactic table to the recording instrument to mimic resting state EEG recordings in preterm humans. In particular, after recovery from the electrode insertion operation (1 week), the animals were accustomed to the recording setup every day for one week before recording. The recorded signal was then segmented into 1-minute fragments and then filtered with a low-pass filter at 100 Hz and subsampled at 100 kHz. After that, the power spectrum of the resulting signal was calculated and the signal powers were calculated for each frequency band of interest. A lower power ratio was found between high and low frequencies in PT mice, indicating higher relative power in the low-frequency bands and lower power in the high-frequency bands. Id) PT mice displayed behavioural and cognitive deficits, similar to those reported in children and adolescents born preterm (Fig. Id).

[0070] To assess behavioural and cognitive deficits in adolescent PT mice, a series of tests assessing repetitive / social behaviour and memory performance was performed. It was found that adolescent PT mice displayed a significant increase in repetitive behaviour in the selfhygiene or "grooming" test, which measures the time spent licking or scratching the head or body parts with any of the forelimbs. In addition, PT mice displayed a significant decrease in sociability in the three-chamber test, which measures time spent with a mouse that has never been met with respect to an object. Finally, PT mice displayed poor spatial memory in the object location (OL) test, which assesses spatial memory by measuring the mice's ability to recognise the new location of a familiar object.

[0071] EXAMPLE 2

[0072] PT mice displayed increased excitability caused by reduced GABA-mediated tonic inhibition in the hippocampal region.

[0073] To assess the intrinsic excitability of pyramidal neurons, patch-clamp recordings were performed on pyramidal neurons in the CAI region of acute hippocampal slices of adolescent PT mice. The pyramidal neurons of PT mice emitted more action potentials (APs) in response to increasing depolarising current injections than those of controls (Fig. 2a, on the left). As a result, adolescent PT mice displayed a significantly lower rheobase (the minimum current required to evoke an AP) than controls (Fig. 2a, on the right). The increase in intrinsic excitability of PT mice is not due to alterations in passive properties (e.g. input resistance) or active properties (e.g. AP threshold). Considering the results on the decrease in the number of interneurons (neurons responsible for GABAergic inhibitory transmission), alterations in GABAergic transmission were evaluated as a possible mechanism behind the increased intrinsic excitability. In particular, since GABA exerts a powerful control over neuronal excitability through the activation of tonic inhibition mediated by extrasynaptic GABAA receptors, GABAergic tonic currents were studied in PT mice and control pups. To reveal GABAergic tonic inhibition, the GABAA receptor antagonist bicuculline (20 pM) was applied in the extracellular recording solution to acute brain slices of adolescent mice. The application of bicuculline reduced the holding current in the neurons undergoing recording (and cancelled spontaneous phasic GABAergic events), revealing a tonically active inhibitory tone. In particular, adolescent PT mice displayed a lower tonic current than controls (Fig. 2b). EXAMPLE 3

[0074] «5-GABAAR PAM GL-II-73 restores behavioural but not cognitive deficits in PT mice.

[0075] To test the ability of a5-GABA PAM, GL-II-73, to restore behavioural and cognitive deficits in PT mice, the grooming test (self-hygiene test) and the object localisation test were performed after drug administration. The mice were treated with GL-II-73 (i.p. 10 mg / kg) or with a carrier. Treatment with GL-II-73 significantly reduced the grooming behaviour of PT mice to the level of control mice (Fig. 3a).

[0076] In addition, the ability of GL-II-73 to lead to an improvement in long-term memory was tested. However, treatment with GL-II-73 was not able to lead to an improvement in cognitive deficits in the PT model. EXAMPLE 4

[0077] Combining a5-GABAAR PAM GL-II-73 with 5-GABAAR PAM Ganaxolone restores cognitive deficits in PT mice

[0078] It was therefore thought that mediators of the GABAergic current in the hippocampus may contain both the a5 and 5 subunit and that it was therefore necessary to act on both receptors to improve cognitive deficits in the PT model. To this end, the object localisation test was performed after administration of a combination of GL-II-73 and ganaxolone, PAM of the 5 subunit of the extra-synaptic GABAA receptor. The mice were treated with GL-II-73 (i.p. 5 mg / kg) together with ganaxolone (i.p. 5 mg / kg) or with a carrier. Treatment with a combination of GL-II-73 and ganaxolone significantly restored spatial memory in the object localisation task (Fig. 3c).

Claims

CLAIMS1.- Pharmaceutical combination comprising a positive allosteric modulator (PAM) of the a5 subunit of the extra- synaptic GABAA receptor and a positive allosteric modulator of the 5 subunit of the extra-synaptic GABAA receptor for use in restoring cognitive and behavioural deficits and improving memory deficits in individuals born preterm, characterised in that said positive allosteric modulator (PAM) of the a5 subunit of the extra-synaptic GABAA receptor is selected from the group consisting of the ethyl ester of (R)-8-ethynyl-6- (2-fluorophenyl)-4-methyl-4H-2,5,10b- triaza-benzo [e]azulene-3-carboxylic acid (SH-053-R-CH3- 2'F), 3- (2,5-difluorophenyl)-7- (1,1-dimethylethyl)-6-[(1- methyl-lH-1,2,4-triazol-5-yl)metoxy] -1,2,4-triazole[4,3- b]pyridazine (L-838,417), 6,6-dimethyl-3- (3- hydroxypropyl)thio-1- (thiazol-2-yl)-6,7-dihydro-2- benzothiophene-4 (5H)-one, NS11821, or pharmaceutically acceptable salts thereof and compounds of formula (I) or a pharmaceutically acceptable salt thereof:wherein:X is selected from the group consisting of N, CH, C-F, C-Cl, C-Br, C-I and C-NO2; Ri is selected from the group consisting of Br, -C=CH, and cyclopropyl;R3 is selected from the group consisting of H, CH3, CH2-CH3, CH(CH3)2, OH, F, Cl, CF3and CC13; andRio and RH are independently selected from the group consisting of H, Cl-6 alkyl, cycloalkyl or taken together with nitrogen form a heterocycloalkyl ring with 3-6 members; and said positive allosteric modulator (PAM) of the 5- subunit of the extra-synaptic GABAA receptor being selected from the group consisting of ganaxolone, gabaxadol, zuranolone, 1- ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy- 3,13-dimethylhexadecaidro-lH-cyclopenta [a]phenanthren-17- yl)-2- (2H-1,2,3-triazol-2-yl)ethan-l-one (SGE-516), 1-[ (3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3- (methoxymethyl)-13-methyl-2,4,5,6,7,8,9,10,11,12,14,15,16,17- tetradecahydro-lH-cyclopenta [a]phenanthren-17-yl]-2- (5- methyltetrazol-2-yl)ethanone (Sage-324), allopregnanolone, brexanolone, LYT-300 or a pharmaceutically acceptable salt thereof.

2. Combination for use according to claim 1, characterised in that X is selected from the group consisting of N, CH and C-F.3.- Combination for use according to claim 1, characterised in that Ri is -C=CH.4.- Combination for use according to claim 1, characterised in that R3 is selected from the group consisting of H and CH3.5.- Combination for use according to claim 1, characterised in that Rio and RH are independently selected from the group consisting of H and Cl-6 alkyl.6.- Combination for use according to claim 1, characterised in that said positive allosteric modulator (PAM) of the a5 subunit of the extra-synaptic GABAA receptor is selected from the group consisting of:7 Combination for use according to claim 1, characterised in that said positive allosteric modulator (PAM) of the a5 subunit of the extra-synaptic GABAA receptoris GL-II-73.8.- Combination for use according to claim 1, characterised in that said positive allosteric modulator of the a5 subunit of the extra-synaptic GABAA receptor is GL- 11-73 and said positive allosteric modulator of the 5 subunit of the extra-synaptic GABAA receptor is ganaxolone.

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