• Article

In Vitro and in Vivo Neuronal Nicotinic Receptor Properties of (+)- and (-)-Pyrido[3,4]homotropane [(+)- and (-)-PHT]


Carroll, F. I., Navarro, H. A., Mascarella, S. W., 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 alpha 6 beta 2 Containing Neuronal Nicotinic Acetylcholine Receptors. ACS Chemical Neuroscience, 6(6), 920-926. DOI: 10.1021/acschemneuro.5b00077, 10.1021/acschemneuro.5b00077


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 [H-3]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 alpha 4 beta 2-nAChRs, relative to alpha 3 beta 4-nAChRs (15-fold) and alpha 7-nAChRs (45-fold). (-)-PHT was an antagonist with selectivity for alpha 3 beta 4, relative to alpha 4 beta 2- (3-fold) and alpha 7- (11-fold) nAChRs. In [H-3]DA release studies in mice, (+)-PHT was 10-fold more potent than (-)-PHT at alpha 4 beta 2*-nAChRs and 30-fold more potent at alpha 6 beta 2*-nAChRs. Studies using alpha 5KO mice suggested that much of the activity at alpha 4 beta 2*-nAChRs is mediated by the alpha 4 beta 2 alpha 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 alpha 6*-nAChR contrasts with the partial agonism observed for alpha 4*-nAChR, making these ligands intriguing probes for learning more about the pharmacophores for various nAChRs.