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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Yenugonda, VM; Xiao, Y; Levin, ED; Rezvani, AH; Tran, T; Al-Muhtasib, N; Sahibzada, N; Xie, T; Wells, C; Slade, S; Johnson, JE; Dakshanamurthy, S; Kong, H-S; Tomita, Y; Liu, Y; Paige, M; Kellar, KJ; Brown, ML

Published Date

  • November 14, 2013

Published In

Volume / Issue

  • 56 / 21

Start / End Page

  • 8404 - 8421

PubMed ID

  • 24047231

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/jm4008455


  • eng

Conference Location

  • United States