In vitro and in vivo neuronal nicotinic receptor properties of (+)- and (-)-pyrido[3,4]homotropane [(+)- and (-)-PHT]: (+)-PHT is a potent and selective full agonist at alpha6beta2 containing neuronal nicotinic acetylcholine receptors
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 efficacy partial agonist selective for ?4?2-nAChRs, relative to ?3?4-nAChRs (15-fold) and ?7-nAChRs (45-fold). (?)-PHT was an antagonist with selectivity for ?3?4, relative to ?4?2- (3-fold) and ?7- (11-fold) nAChRs. In [3H]DA release studies in mice, (+)-PHT was 10-fold more potent than (?)-PHT at ?4?2*-nAChRs and 30-fold more potent at ?6?2*-nAChRs. Studies using ?5KO mice suggested that much of the activity at ?4?2*-nAChRs is mediated by the ?4?2?5-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 ?6*-nAChR contrasts with the partial agonism observed for ?4*-nAChR, making these ligands intriguing probes for learning more about the pharmacophores for various nAChRs.