In Vitro and in Vivo Neuronal Nicotinic Receptor Properties of (+)- and (鈭?-Pyrido[3,4]homotropane [(+)- and (鈭?-PHT]: (+)-PHT Is a Potent and Selective Full Agonist at 伪6尾2 Containing Neuronal Nicoti

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• 作者：F. Ivy Carroll ; Hern谩n A. Navarro ; S. Wayne Mascarella ; Ana H. Castro ; Charles W. Luetje ; Charles R. Wageman ; Michael J. Marks ; Asti Jackson ; M. Imad Damaj
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：June 17, 2015
• 年：2015
• 卷：6
• 期：6
• 页码：920-926
• 全文大小：248K
• ISSN：1948-7193

文摘

Pyrido[3,4]homotropane (PHT) is a conformationally rigid, high affinity analogue of nicotine. (+)-PHT was previously shown to be 266 times more potent than (鈭?-PHT for inhibition of [³H]epibatidine binding to nAChRs but had no antinociceptive activity in mouse tail-flick or hot-plate tests and was not a nicotinic antagonist even when administered intrathecally. While (鈭?-PHT had no agonist activity, it was a potent, nicotinic antagonist in the test. Here, electrophysiological studies with rat nAChRs show (+)-PHT to be a low efficacy partial agonist selective for 伪4尾2-nAChRs, relative to 伪3尾4-nAChRs (15-fold) and 伪7-nAChRs (45-fold). (鈭?-PHT was an antagonist with selectivity for 伪3尾4, relative to 伪4尾2- (3-fold) and 伪7- (11-fold) nAChRs. In [³H]DA release studies in mice, (+)-PHT was 10-fold more potent than (鈭?-PHT at 伪4尾2*-nAChRs and 30-fold more potent at 伪6尾2*-nAChRs. Studies using 伪5KO mice suggested that much of the activity at 伪4尾2*-nAChRs is mediated by the 伪4尾2伪5-nAChR subtype. In conditioned place preference studies, (鈭?-PHT was more potent than (+)-PHT in blocking nicotine reward. Off-target screens showed (+)- and (鈭?-PHT to be highly selective for nAChRs. The high potency, full agonism of (+)- and (鈭?-PHT at 伪6*-nAChR contrasts with the partial agonism observed for 伪4*-nAChR, making these ligands intriguing probes for learning more about the pharmacophores for various nAChRs.