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J Med Chem. 2013 Nov 14;56(21):8404-21. doi: 10.1021/jm4008455. Epub 2013 Oct 18.

Design, synthesis and discovery of picomolar selective α4β2 nicotinic acetylcholine receptor ligands.

Author information

1
Center for Drug Discovery, Georgetown University Medical Center , 3970 Reservoir Road NW, Research Building, EP-07, Washington, D.C. 20057, United States.

Abstract

Developing novel and selective compounds that desensitize α4β2 nicotinic acetylcholine receptors (nAChRs) could provide new effective treatments for nicotine addiction, as well as other disorders. Here we report a new class of nAChR ligands that display high selectivity and picomolar binding affinity for α4β2 nicotinic receptors. The novel compounds have Ki values in the range of 0.031-0.26 nM and properties that should make them good candidates as drugs acting in the CNS. The selected lead compound 1 (VMY-2-95) binds with high affinity and potently desensitizes α4β2 nAChRs. At a dose of 3 mg/kg, compound 1 significantly reduced rat nicotine self-administration. The overall results support further characterizations of compound 1 and its analogues in preclinical models of nicotine addiction and perhaps other disorders involving nAChRs.

PMID:
24047231
DOI:
10.1021/jm4008455
[Indexed for MEDLINE]

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