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 α6β2 Containing Neuronal Nicotinic Acetylcholine Receptors

F. Ivy Carroll, Hernán A. Navarro, S. Wayne Mascarella, Ana H. Castro, Charles W. Luetje, Charles R. Wageman, Michael J. Marks, Asti Jackson, M. Imad Damaj

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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 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.

Original languageEnglish (US)
Pages (from-to)920-926
Number of pages7
JournalACS Chemical Neuroscience
Issue number6
StatePublished - Jun 17 2015



  • (-)- and (+)-PHT
  • (-)- and (+)-Pyrido[3,4]homotropane
  • [<sup>3</sup>H]dopamine release studies
  • conditioned place preference studies
  • electrophysiological studies
  • nicotinic receptors
  • α6β2-nicotine agonist

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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