Compositions and methods for treatment of neurological disorders

Abstract

The present invention concerns methods for treating or preventing neurological disorders characterized by dysfunction of nicotine acetylcholine receptors by co-administration of metanicotine and at least one compound which exhibits antagonist activity, or both agonistic and antagonist activity, toward one or more nicotinic acetylcholine receptor subtypes. The subject invention, in another aspect, pertains to pharmaceutical compositions containing metanicotine and at least one compound which exhibits antagonistic activity, or both agonistic and antagonistic activity, toward one or more nicotinic acetylcholine receptor subtypes.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] The present application is a continuation of U.S. application Ser. No. 10 / 036,988, filed Dec. 31, 2001, which is hereby incorporated by reference herein in its entirety, including any figures, tables, nucleic acid sequences, amino acid sequences, or drawings.GOVERNMENT SUPPORT [0002] The subject invention was made with government support under a research project supported by National Institutes of Health Grant No. PO1 AG10485. The government has certain rights in this invention.BACKGROUND OF THE INVENTION [0003] The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The ion channel is formed from the assembly of a membrane protein oligomer (a pentamer) that binds the neurotransmitter, acetylcholine, its natural ligand. The nAChR also binds agonists, such as nicotine, and nicotinic antagonists, such as mecamylamine. The binding of two mole...

AI Technical Summary

Benefits of technology

[0012] The subject invention concerns methods of treating a patient suffering from a neurological condition characterized by the dysfunction of nAChRs by the co-administration of a metanicotine, or a pharmaceutically acceptable salt or analogue thereof, and a compound having either: (1) an antagonist profile of action toward one or more nAChR subtypes; or (2) a mixed agonist / antagonist profile of action toward one or more nAChR subtypes. The metanicotine and the nAChR antagonist or mixed nAChR agonist / antagonist can be simultaneously administered or consecutively administered. If administered simultaneously, the metanicotine and the nAChR antagonist, or the metanicotine and the mixed nAChR agonist / antagonist, can be administered as separate compounds, or administered together as a pharmaceutical composition of the subject invention. Therefore, in another aspect, the subject invention also pertains to pharmaceutical compositions containing metanicotine, or a pharmaceutically acceptable salt or analogue thereof, and an nAChR antagonist or mixed nAChR agonist / antagonist. The combination of nicotinic receptor ligands, incorporating metanicotine and a mixed agonist / antagonist or metanicotine and an nAChR antagonist, results in the reduction or elimination of undesirable effects that would otherwise be associated with administration of the mixed agonist / antagonist alone or the antagonist alone. This innovative approach facilitates the development of therapies for a number of neurological disorders, with improved selectivity for nAChR subtypes. Thus, the methods of the subject invention provide a therapeutic window for utilization of such nAChR antagonists or mixed agonists / antagonists in the treatment of neurological conditions where one previously did not exist.

[0014] Metanicotine is an effective activator of the α4β2 neuronal nAChR subtype, with activity comparable with that of acetylcholine (ACh) (Bencherif, M. et al., J. Pharmacol. Exp. Ther. [1996] 279:1413-1421; Lippiello, P. M. et al., J. Pharmacol. Exp. Ther. [1996] 279:1422-1429). Furthermore, metanicotine can be distinguished from nicotine and other mixed agonists / antagonists by the relatively low level of residual inhibition (or desensitization) that occurs after receptor activation (Papke et al., J. Neurochem. [2000] 75(1):204-216). Although metanicotine is particularly useful in the methods and compositions of the present invention for its ability to reduce the inhibitory effects of nAChR antagonists or mixed nAChR agonists / antagonists, therapeutic effect can also be derived from the nAChR agonistic activity exhibited by metanicotine itself.

[0016] The fact that metanicotine can protect nicotinic receptors from the inhibitory after-effects of other potentially therapeutic agonists is of great clinical significance. The subject invention permits the tuning of the selectivity of specific compounds to increase desired effects and diminish side effects. In this way, co-administration of metanicotine with other compounds can provide a means to tune a spectrum of effects to enhance receptor subtype-selective activation, thereby producing a more positive profile of effects. In one embodiment, metanicotine and / or the mixed nAChR agonist / antagonist interact with one or more of the nAChR α2-α10 and β2-β4 subunits. In another embodiment, metanicotine and / or the mixed nAChR agonist / antagonist interact with heteromeric nAChR subunit combinations of α2-α6 and β2-β10, homomeric nAChR subunit combinations of α7-α10, or both. In a further embodiment, metanicotine and / or the nAChR antagonist interact with one or more of the nAChR α2-α10 and β2-β4 subunits.

Problems solved by technology

With these newly defined therapeutic endpoints, the challenge becomes understanding how best to target nicotinic drugs to the receptor systems of the brain.

The pharmacology of neuronal nicotinic receptors, however, is very complex.

Furthermore, nicotinic receptor subunits exhibit considerable promiscuity in their ability to coassemble to form functional channels in various expression systems.

Unfortunately, subtype selective agonists and antagonists have been only slowly forthcoming.

Unfortunately, because of their mixed agonist / antagonist profiles, the toxic side effects produced by these agents hinder their development as therapeutic drugs.

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