2-, 5-, and 6-halo-3-(2(S)-azetidinylmethoxy)pyridines:: Synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling
2-, 5-, and 6-halo-3-(2(S)-azetidinylmethoxy)pyridines:: Synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling
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DOI：
10.1021/jm980170a
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发表时间：
1998-09-10
影响因子：
7.3
通讯作者：
London, ED
中科院分区：
文献类型：
--
作者：
Koren, AO;Horti, AG;London, ED
3-（2（S）-氮杂环丁烷甲氧基）吡啶（A-85380）是近年来发现的一种与烟碱乙酰胆碱受体（nAChR）具有高亲和力的配体。在这里，我们报告的合成和体外nAChR结合的一系列的10个吡啶修饰的类似物A-85380;新的化合物的特点是卤素取代基的位置2，5，或6的3-吡啶片段。在5或6位具有取代基的那些，以及2-氟类似物，对大鼠脑膜中的nAChRs具有亚纳摩尔的亲和力。对于这些配体，Ki值范围为11至210 pM，如通过与（+/-）-[H-3]地棘蛙素竞争所测量的。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。AM 1量子化学计算表明，在位置2的庞大的取代基引起的分子几何结构的显着变化。该系列的高亲和力成员和（+）-地棘蛙素显示出低能稳定构象的紧配合叠加。具有高亲和力的nAChRs的新的配体可能是感兴趣的药理学探针，潜在的药物，和开发放射性卤代示踪剂研究nAChRs的候选人。
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, K-i values range from 11 to 210 pM, as measured by competition with (+/-)-[H-3]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.