Ayers Joshua T, Dwoskin Linda P, Deaciuc A Gabriela, Grinevich Vladimir P, Zhu Jun, Crooks Peter A
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Bioorg Med Chem Lett. 2002 Nov 4;12(21):3067-71. doi: 10.1016/s0960-894x(02)00687-x.
A series of bis-nicotinium, bis-pyridinium, bis-picolinium, bis-quinolinium and bis-isoquinolinium compounds was evaluated for their binding affinity at nicotinic acetylcholine receptors (nAChRs) using rat brain membranes. N,N'-Decane-1,12-diyl-bis-nicotinium diiodide (bNDI) exhibited the highest affinity for [(3)H]nicotine binding sites (K(i)=330 nM), but did not inhibit [(3)H]methyllycaconitine binding (K(i) >100 microM), indicative of an interaction with alpha4beta2*, but not alpha7* receptor subtypes, respectively. Also, bNDI inhibited (IC(50)=3.76 microM) nicotine-evoked (86)Rb(+) efflux from rat thalamic synaptosomes, indicating antagonist activity at alpha4beta2* nAChRs. N,N'-Dodecane-1,12-diyl-bis-quinolinium dibromide (bQDDB) exhibited highest affinity for [(3)H]methyllycaconitine binding sites (K(i)=1.61 microM), but did not inhibit [(3)H]nicotine binding (K(i)>100 microM), demonstrating an interaction with alpha7*, but not alpha4beta2* nAChRs. Thus, variation of N-n-alkyl chain length together with structural modification of the azaaromatic quaternary ammonium moiety afforded selective antagonists for the alpha4beta2* nAChR subtype, as well as ligands with selectivity at alpha7* nAChRs.
使用大鼠脑膜评估了一系列双烟碱鎓、双吡啶鎓、双皮考啉鎓、双喹啉鎓和双异喹啉鎓化合物对烟碱型乙酰胆碱受体（nAChRs）的结合亲和力。N,N'-癸烷-1,12-二基-双烟碱鎓二碘化物（bNDI）对[(3)H]尼古丁结合位点表现出最高亲和力（K(i)=330 nM），但不抑制[(3)H]甲基番木鳖碱结合（K(i)>100 microM），分别表明其与α4β2而非α7受体亚型相互作用。此外，bNDI抑制（IC(50)=3.76 microM）尼古丁诱发的大鼠丘脑突触体中(86)Rb(+)外流，表明其对α4β2* nAChRs具有拮抗剂活性。N,N'-十二烷-1,12-二基-双喹啉鎓二溴化物（bQDDB）对[(3)H]甲基番木鳖碱结合位点表现出最高亲和力（K(i)=1.61 microM），但不抑制[(3)H]尼古丁结合（K(i)>100 microM），证明其与α7而非α4β2 nAChRs相互作用。因此，N-正烷基链长度的变化以及氮杂芳族季铵部分的结构修饰提供了α4β2* nAChR亚型的选择性拮抗剂以及对α7* nAChRs具有选择性的配体。
