title: 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.
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 [(3)H]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 [(3)H]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.
authors.affiliation: †Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.affiliation: †Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.affiliation: †Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.affiliation: ‡Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33101, United States.
authors.forename: Ana H
authors.initials: AH
authors.lastname: Castro
authors.affiliation: ‡Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33101, United States.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Luetje
authors.affiliation: §Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, United States.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wageman
authors.affiliation: §Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.affiliation: ∥Department of Pharmacology, Virginia Commonwealth University Medical Campus, P.O. Box 980615, Richmond, Virginia 23298-0613, United States.
authors.forename: Asti
authors.initials: A
authors.lastname: Jackson
authors.affiliation: ∥Department of Pharmacology, Virginia Commonwealth University Medical Campus, P.O. Box 980615, Richmond, Virginia 23298-0613, United States.
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014326:Tropanes / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D014326:Tropanes; C559463:alpha6beta2 nicotinic acetylcholine receptor; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; C055134:pyrido(3,4-b)norhomotropane; D004298:Dopamine
keywords: (−)- and (+)-PHT; (−)- and (+)-Pyrido[3,4]homotropane; [3H]dopamine release studies; conditioned place preference studies; electrophysiological studies; nicotinic receptors; α6β2-nicotine agonist