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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.

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


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.

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