Compositions and methods for treatment of neurological disorders

Inactive Publication Date: 2005-01-20
FLORIDA UNIV OF A FLORIDA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[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 p

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 t

Method used

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  • Compositions and methods for treatment of neurological disorders
  • Compositions and methods for treatment of neurological disorders
  • Compositions and methods for treatment of neurological disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Beta Subunit TM2 Mutations Promote Agonist-Induced Residual Inhibition by ACh and Nicotine

[0062] As previously reported for receptors containing chimeric β4 subunits (Webster, J. C. et al., Br. J. of Pharmacol. [1999] 127:1337-1348), receptors containing the β4 6′ and 10′ point mutations showed decreased responses to repeated applications of ACh and nicotine, suggesting that these agonists produce some form of residual inhibition, as shown in FIGS. 1A and 1B. While the inhibition produced by nicotine persisted for up to an hour (not shown), inhibition produced by ACh was more reversible, with essentially full recovery after 7-8 minutes of wash.

[0063] The concentration-response function for nicotine's activation and inhibition of wild-type and mutant receptors is shown in FIGS. 2A and 2B. The presence of the 6′ and 10′ mutations in the β4 subunit appeared to increase the efficacy of nicotine compared to ACh and to substantially increase the agonist-induced residual inhibition measu...

example 2

TM2 Mutations Differentially Regulate the Activation and Inhibition of Subtype-Selective Agonists

[0064] As shown in FIGS. 2A and 2B, the 6′ / 10′ mutations appear to influence both activation and agonist-induced residual inhibition, raising the question of whether these effects are likely to represent multiple consequences of these agonists binding to a single site on the receptor (i.e. the activation binding site), or alternatively represent effects from binding to multiple sites on the receptors. In order to test this, the effects of other agonists on the wild-type and mutant receptors were investigated. Specifically, two subtype-selective agents were used that previously have been reported to be only weak partial agonists on wild-type α3β4 receptors, DMXB and TC-2403 (metanicotine). DMXB is an α7-selective partial agonist (Meyer, E. M. et al., Brain Res. [1997] 768:49-56) that can produce agonist-induced residual inhibition of wild-type receptors in the absence of strong activatio...

example 3

The Residual Inhibition Produced by Agonists is Voltage Dependent

[0066] The voltage dependence of the residual inhibition of wild-type α3β4 and α3β4(6′F10′T) receptors produced by DMXB was evaluated, as well as the enhanced inhibition of α3β4(6′F10′T) mutant receptors by nicotine and ACh to see if the inhibition had properties that would be consistent with open channel blockade. Cells were held at either −50 mV or −100 mV and tested for their response to control concentrations of ACh. After a 10 min wash, test agonists (ACh, DMXB or nicotine) were applied at the concentrations indicated. Cells were then washed for 5 min and tested again for their response to a control ACh application. Cells were held at the indicated holding potential throughout the entire procedure. As shown in FIGS. 4A and 4B, the residual inhibition of both wild-type and mutant receptors was enhanced if the cells were held at a hyperpolarized potential. This would be consistent with inhibition associated with bi...

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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...

Claims

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Application Information

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IPC IPC(8): A61K31/22A61K31/4545A61K31/465
CPCA61K31/22A61K31/4545A61K31/465A61K2300/00
Inventor PAPKE, ROGER
Owner FLORIDA UNIV OF A FLORIDA
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