Compounds capable of activating cholinergic receptors

a technology compounds, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocides, etc., can solve the problems of not providing significant side effects, and achieve the effects of increasing the number of nicotinic cholinergic receptors of the brain of the patient, preventing and suppressing symptoms, and increasing blood pressure and heart ra

Inactive Publication Date: 2005-06-16
CALDWELL WILLIAM SCOTT +6
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] The pharmaceutical compositions of the present invention are useful for the prevention and treatment of disorders, such as CNS disorders, which are characterized by an alteration in normal neurotransmitter release. The pharmaceutical compositions provide therapeutic benefit to individuals suffering from such disorders and exhibiting clinical manifestations of such disorders in that the compounds within those compositions, when employed in effective amounts, have the potential to (i) exhibit nicotinic pharmacology and affect relevant nicotinic receptors sites (e.g., act as a pharmacological agonist to activate nicotinic receptors), and (ii) elicit neurotransmitter secretion, and hence p

Problems solved by technology

It would be highly beneficial to provide individuals suffering from certain disorders (e.g., CNS diseases) with interruption of the symptoms of those disorders by the administration of a pharmaceutical composi

Method used

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  • Compounds capable of activating cholinergic receptors
  • Compounds capable of activating cholinergic receptors

Examples

Experimental program
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Effect test

example 1

Determination of Log P Value

[0038] Log P values, which have been used to assess the relative abilities of compounds to pass across the blood-brain banrier (Hansch, et al., J. Med. Chem. ii:1 (1968)), were calculated using the Cerius2 software package Version 3.5 by Molecular Simulations, Inc.

example 2

Determination of Binding to Relevant Receptor Sites

[0039] Binding of the compounds to relevant receptor sites was determined in accordance with the techniques described in U.S. Pat. No. 5,597,919 to Dull et al. Inhibition constants (Ki values), reported in nM, were calculated from the IC50 values using the method of Cheng et al., Biochem, Pharmacol. 22:3099 (1973).

example 3

Determination of Dopamine Release

[0040] Dopamine release was measured using the techniques described in U.S. Pat. No. 5,597,919 to Dull et al. Release is expressed as a percentage of release obtained with a concentration of (S)-(−)-nicotine resulting in maximal effects. Reported EC50 values are expressed in nM, and Emax values represent the amount released relative to (S)-(−)-nicotine on a percentage basis.

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Abstract

Compounds incorporating aryl substituted olefinic amine are provided. Representative compounds are (4E)-N-methyl-5-(3-pyridyl)4-penten-2-amine, (4E)-N-methyl-5-(5-pyrimidinyl)4-penten-2-amine, (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine, (2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine, (2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine and (2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

Description

RELATED APPLICATIONS [0001] This application is a continuation of pending U.S. application Ser. No. 09 / 522,117 filed Mar. 9, 2000 (pending); which is a continuation of U.S. application Ser. No. 09 / 098,285, filed Jun. 16, 1998 (abandoned), the disclosures of which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION [0002] The present invention relates to compounds capable of activating nicotinic cholinergic receptors, for example, as agonists of specific nicotinic receptor subtypes. [0003] Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al. N. Engl. J. Med. 330:811-815 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See for example, Sjak-shie et al., Brain Res. 624:295 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem. ...

Claims

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Application Information

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IPC IPC(8): A61K31/44A61K31/505C07D213/38C07D213/61C07D213/65C07D213/73C07D239/26
CPCA61K31/44A61K31/505C07D213/38C07D239/26C07D213/65C07D213/73C07D239/24C07D213/61A61P25/14A61P25/16A61P25/18A61P25/28
Inventor CALDWELL, WILLIAM SCOTTDULL, GARY MAURICEBHATTI, BALWINDER SINGHHADIMANI, SRISHAILKUMAR B.PARK, HAEILWAGNER, JARED MILLERCROOKS, PETER ANTHONY
Owner CALDWELL WILLIAM SCOTT
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