In Vitro and in Vivo Neuronal Nicotinic Receptor Properties of (+)and (−)-Pyrido34homotropane (+)- and (−)-PHT: (+)-PHT Is a Potent and Selective Full Agonist at α6β2 Containing Neuronal Nicotinic Acetylcholine Receptors

摘要

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 (−)-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 (−)-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 eficacy partial agonist selective for α4β2-nAChRs, relative to α3β4-nAChRs (15-fold) and α7-nAChRs (45-fold). (−)-PHT was an antagonist with selectivity for α3β4, relative to α4β2-(3-fold) and α7- (11-fold) nAChRs. In [³H]DA release studies in mice, (+)-PHT was 10-fold more potent than (−)-PHT at α4β2*-nAChRs and 30-fold more potent at α6β2*-nAChRs. Studies using α5KO mice suggested that much of the activity at α4β2*-nAChRs is mediated by the α4β2α5-nAChR subtype. In conditioned place preference studies, (−)-PHT was more potent than (+)-PHT in blocking nicotine reward. Off-target screens showed (+)- and (−)-PHT to be highly selective for nAChRs. The high potency, full agonism of (+)- and (−)-PHT at α6*-nAChR contrasts with the partial agonism observed for α4*-nAChR, making these ligands intriguing probes for learning more about the pharmacophores for various nAChRs.