1区 · 医学
Article
作者: Xie, Teresa ; Rezvani, Amir H. ; Levin, Edward D. ; Liu, Yong ; Kellar, Kenneth J. ; Wells, Corinne ; Tomita, York ; Paige, Mikell ; Yenugonda, Venkata M. ; Xiao, Yingxian ; Brown, Milton L. ; Dakshanamurthy, Sivanesan ; Slade, Susan ; Tran, Thao ; Johnson, Joshua E. ; Al-Muhtasib, Nour ; Sahibzada, Niaz ; Kong, Hye-Sik
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.