Center for Organic and Medicinal Chemistry, Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
J Med Chem. 2014 Feb 13;57(3):836-48. doi: 10.1021/jm401602p. Epub 2014 Jan 28.
2'-Fluoro-3-(substituted pyridine)epibatidine analogues 7a-e and 8a-e were synthesized, and their in vitro and in vivo nAChR properties were determined. 2'-Fluoro-3'-(4″-pyridinyl)deschloroepibatidine (7a) and 2'-fluoro-3'-(3″-pyridinyl)deschloroepibatidine (8a) were synthesized as bioisosteres of the 4'-nitrophenyl lead compounds 5a and 5g. Comparison of the in vitro nAChR properties of 7a and 8a to those of 5a and 5g showed that 7a and 8a had in vitro nAChR properties similar to those of 5a and 5g but both were more selective for the α4β2-nAChR relative to the α3β4- and α7-nAChRs than 5a and 5g. The in vivo nAChR properties in mice of 7a were similar to those of 5a. In contrast, 8a was an agonist in all four mouse acute tests, whereas 5g was active only in a spontaneous activity test. In addition, 5g was a nicotine antagonist in both the tail-flick and hot-plate tests, whereas 8a was an antagonist only in the tail-flick test.
2'-氟-3-(取代吡啶基)埃派他丁类似物 7a-e 和 8a-e 被合成，并测定了它们的体外和体内烟碱型乙酰胆碱受体(nAChR)性质。2'-氟-3'-(4″-吡啶基)去氯埃派他丁(7a)和 2'-氟-3'-(3″-吡啶基)去氯埃派他丁(8a)被合成作为 4'-硝基苯铅化合物 5a 和 5g 的生物等排体。比较 7a 和 8a 的体外 nAChR 性质与 5a 和 5g 的性质，发现 7a 和 8a 具有与 5a 和 5g 相似的体外 nAChR 性质，但相对于 α3β4-和 α7-nAChR，它们对 α4β2-nAChR 的选择性均高于 5a 和 5g。7a 在小鼠体内的 nAChR 性质与 5a 相似。相比之下，8a 在所有四种小鼠急性试验中均为激动剂，而 5g 仅在自发活动试验中具有活性。此外，5g 在尾部闪烁和热板试验中均为尼古丁拮抗剂，而 8a 仅在尾部闪烁试验中为拮抗剂。
