Design, Synthesis, and Preliminary Pharmacological Evaluation of New Quinoline Derivatives as Nicotinic Ligands

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• 作者：Luca Guandalini ; Monica Norcini ; Katia Varani ; Marco Pistolozzi ; Cecilia Gotti ; Carla Bazzicalupi ; Elisabetta Martini ; Silvia Dei ; Dina Manetti ; Serena Scapecchi ; Elisabetta Teodori ; Carlo Bertucci ; C
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：4993 - 5002
• 全文大小：159K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

文摘

A series of nicotinic ligands, carrying a quinoline nucleus, and characterized by a pharmacophoric distancebetween the quinoline nitrogen (H-bond acceptor) and the cationic nitrogen atoms higher than that proposedin the classical pharmacophoric models, have been synthesized and tested for their affinity for the centralnicotinic receptor. The enantiomers of the nicotine analogue 1-methyl-2-pyrrolidinyl-6-quinoline and of itsmethiodide display enantioselectivity in binding studies, but not when tested in vivo; on 7* nicotinic receptorenantioselectivity is inverted with respect to the 42* subtype. N,N,N-Trimethyl-4-(quinolin-6-yl)but-3-yn-1-ammonium iodide (3c) and trans-N,N,N-trimethyl-4-(quinolin-6-yl)but-3-en-1-ammonium iodide (4c),showing pharmacophoric distances in the range 8.5-10.4 Å, interact with the 42* nicotinic receptorwith K_i in the M range; compound 3c shows preference for the 7* subtype.