Abreo M A, Lin N H, Garvey D S, Gunn D E, Hettinger A M, Wasicak J T, Pavlik P A, Martin Y C, Donnelly-roberts D L, Anderson D J, Sullivan J P, Williams M, Arneric S P, Holladay M W
Pharmaceutical products division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
J Med Chem. 1996 Feb 16;39(4):817-25. doi: 10.1021/jm9506884.
Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotine acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca.50 pM affinity for rat brain [(3)H]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human alpha4beta2 nAChR subtype, and A-84543 (2a), which exhibits 84-fold selectivity to stimulate ion flux at human alpha4beta2 nAchR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4A with (S)-nicotine and (-)-epibatidine can be achieved.
近期证据表明胆碱能通道调节剂在治疗中枢神经系统（CNS）疾病方面具有治疗潜力，同时脑神经元烟碱型乙酰胆碱受体（nAChRs）具有多样性，这提示了开发亚型选择性nAChR配体以治疗特定CNS疾病并减少副作用的机会。我们报道了一系列新型的3-吡啶基醚化合物，它们对脑nAChRs具有亚纳摩尔亲和力，并能差异性地激活神经元nAChR亚型。描述了该系列主要成员的合成及构效关系，包括A-85380（4a），其对大鼠脑[（3）H]-（-）-金雀花碱结合位点具有约50 pM的亲和力，与尼古丁相比，在人α4β2 nAChR亚型上刺激离子通量的效能为163%；以及A-84543（2a），与人类神经节型nAChRs相比，其在人α4β2 nAchR亚型上刺激离子通量具有84倍的选择性。计算研究表明，4A的低能构象与（S）-尼古丁和（-）-依博加碱可以实现合理的叠加。
