Koren A O, Horti A G, Mukhin A G, Gündisch D, Kimes A S, Dannals R F, London E D
Brain Imaging Center, Intramural Research Program, National Institute on Drug Abuse, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
J Med Chem. 1998 Sep 10;41(19):3690-8. doi: 10.1021/jm980170a.
3-(2(S)-Azetidinylmethoxy)pyridine (A-85380) has been identified recently as a ligand with high affinity for nicotinic acetylcholine receptors (nAChRs). Here we report the synthesis and in vitro nAChR binding of a series of 10 pyridine-modified analogues of A-85380. The novel compounds feature a halogen substituent at position 2, 5, or 6 of the 3-pyridyl fragment. Those with the substituents at position 5 or 6, as well as the 2-fluoro analogue, possess subnanomolar affinity for nAChRs in membranes from rat brain. For these ligands, Ki values range from 11 to 210 pM, as measured by competition with (+/-)-[3H]epibatidine. In contrast, 2-chloro, 2-bromo, and 2-iodo analogues exhibit substantially lower affinity. AM1 quantum chemical calculations demonstrate that the bulky substituents at position 2 cause notable changes in the molecular geometry. The high-affinity members of the series and (+)-epibatidine display a tight fit superposition of low-energy stable conformers. The new ligands with high affinity for nAChRs may be of interest as pharmacological probes, potential medications, and candidates for developing radiohalogenated tracers to study nAChRs.
3-(2(S)-氮杂环丁烷基甲氧基)吡啶(A - 85380)最近被鉴定为一种对烟碱型乙酰胆碱受体(nAChRs)具有高亲和力的配体。在此，我们报告了一系列10种A - 85380吡啶修饰类似物的合成及其体外nAChR结合情况。这些新型化合物在3 - 吡啶基片段的2、5或6位具有卤素取代基。那些在5或6位带有取代基的化合物以及2 - 氟类似物，对大鼠脑膜中的nAChRs具有亚纳摩尔亲和力。对于这些配体，通过与(+/-)-[3H]依博加碱竞争测定，其Ki值范围为11至210 pM。相比之下，2 - 氯、2 - 溴和2 - 碘类似物表现出显著较低的亲和力。AM1量子化学计算表明，2位的大体积取代基会导致分子几何形状发生显著变化。该系列中的高亲和力成员和(+)-依博加碱显示出低能量稳定构象的紧密叠加。这些对nAChRs具有高亲和力的新配体作为药理学探针、潜在药物以及开发用于研究nAChRs的放射性卤化示踪剂的候选物可能会受到关注。
