• Journal Article

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

Citation

Carroll, F., Navarro, H., Mascarella, S., Castro, A. H., Luetje, C. W., Wageman, C. R., ... Damaj, M. I. (2015). 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. ACS Chemical Neuroscience, 6(6), 920-926. DOI: 10.1021/acschemneuro.5b00077

Abstract

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.