Design, Synthesis and Discovery of Picomolar Selective 伪4尾2 Nicotinic Acetylcholine Receptor Ligands

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• 作者：Venkata M. Yenugonda ; Yingxian Xiao ; Edward D. Levin ; Amir H. Rezvani ; Thao Tran ; Nour Al-Muhtasib ; Niaz Sahibzada ; Teresa Xie ; Corinne Wells ; Susan Slade ; Joshua E. Johnson ; Sivanesan Dakshanamurthy ; Hye-Sik Kong ; York Tomita ; Yong Liu ; Mikell Paige ; Kenneth J. Kellar ; Milton L. Brown
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8404-8421
• 全文大小：744K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

Developing novel and selective compounds that desensitize 伪4尾2 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 伪4尾2 nicotinic receptors. The novel compounds have K_i values in the range of 0.031鈥?.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 伪4尾2 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.