Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A

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• 作者：Yong Liu^a ; Mikell Paige^a ; Thao T. Olson^b ; Nour Al-Muhtasib^b ; Teresa Xie^b ; Shujie Hou^a ; Michael P. White^a ; Antoinette Cordova^a ; Jessica L. Guo^a ; Kenneth J. Kellar^b ; Yingxian Xiao^b ; ^{yxiao02@georgetown.edu" class="auth_mail} ; Milton L. Brown^a ; ^{mb544@georgetown.edu" class="auth_mail}
• 关键词：Sazetidine A ; nAChR 伪4尾2 ; Nicotinic receptor ; Click chemistry ; Bioisostere ; Biostere ; Photoaffinity label
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 July 2014
• 年：2014
• 卷：24
• 期：13
• 页码：2954-2956
• 全文大小：583 K

文摘

The enantiomers of two analogs of Sazetidine-A as well as several other novel biosteric analogues were synthesized. Their binding affinities at three major nAChRs subtypes and selectivity profiles were determined. Though many (S)-enantiomers of Sazetidine-A analogs have high binding affinities and good subtype selectivities, it is not a general rule that (S)-enantiomers are better than their (R) counterparts. Compound 11, of which the ethynyl group was replaced by its’ bioisostere—the triazole via click chemistry, showed a high binding affinity to 伪4尾2 subtype (K_i = 1.3 nM) and better selectivity to the 伪4尾2 subtype over 伪3尾4 subtype with that of Sazetidine-A. The azide compound 15, a potential photoaffinity label, showed improved high selectivity and similar binding property profile with that of Sazetidine-A. The biaryl analog 17 exhibited a much lower affinity as compared to Sazetidine-A indicating the importance of a ‘long tail’ side chain for 伪4尾2 nAChR binding.