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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.

التفاصيل البيبلوغرافية
العنوان: 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.
المؤلفون: Carroll FI; †Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States., Navarro HA; †Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States., Mascarella SW; †Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States., Castro AH; ‡Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33101, United States., Luetje CW; ‡Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33101, United States., Wageman CR; §Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, United States., Marks MJ; §Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, United States., Jackson A; ∥Department of Pharmacology, Virginia Commonwealth University Medical Campus, P.O. Box 980615, Richmond, Virginia 23298-0613, United States., Damaj MI; ∥Department of Pharmacology, Virginia Commonwealth University Medical Campus, P.O. Box 980615, Richmond, Virginia 23298-0613, United States.
المصدر: ACS chemical neuroscience [ACS Chem Neurosci] 2015 Jun 17; Vol. 6 (6), pp. 920-6. Date of Electronic Publication: 2015 Apr 30.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101525337 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1948-7193 (Electronic) Linking ISSN: 19487193 NLM ISO Abbreviation: ACS Chem Neurosci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society
مواضيع طبية MeSH: Neurons/*drug effects , Neurons/*metabolism , Nicotinic Agonists/*pharmacology , Pyridines/*pharmacology , Receptors, Nicotinic/*metabolism , Tropanes/*pharmacology, Animals ; Conditioning, Psychological/drug effects ; Conditioning, Psychological/physiology ; Corpus Striatum/drug effects ; Corpus Striatum/metabolism ; Dopamine/metabolism ; Dose-Response Relationship, Drug ; Male ; Mice, Inbred ICR ; Molecular Structure ; Nicotinic Agonists/chemistry ; Nicotinic Antagonists/chemistry ; Nicotinic Antagonists/pharmacology ; Pyridines/chemistry ; Rats ; Spatial Behavior/drug effects ; Spatial Behavior/physiology ; Synaptosomes/drug effects ; Synaptosomes/metabolism ; Tropanes/chemistry ; Xenopus laevis ; alpha7 Nicotinic Acetylcholine Receptor/metabolism
مستخلص: 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.
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معلومات مُعتمدة: R01 DA003194 United States DA NIDA NIH HHS; DA12001 United States DA NIDA NIH HHS; DA003194 United States DA NIDA NIH HHS; R01 DA012001 United States DA NIDA NIH HHS; R01 DA012970 United States DA NIDA NIH HHS; P30 DA015663 United States DA NIDA NIH HHS; R01 DA016327 United States DA NIDA NIH HHS
فهرسة مساهمة: Keywords: (−)- and (+)-PHT; (−)- and (+)-Pyrido[3,4]homotropane; [3H]dopamine release studies; conditioned place preference studies; electrophysiological studies; nicotinic receptors; α6β2-nicotine agonist
المشرفين على المادة: 0 (Nicotinic Agonists)
0 (Nicotinic Antagonists)
0 (Pyridines)
0 (Receptors, Nicotinic)
0 (Tropanes)
0 (alpha6beta2 nicotinic acetylcholine receptor)
0 (alpha7 Nicotinic Acetylcholine Receptor)
0 (nicotinic receptor alpha3beta4)
0 (pyrido(3,4-b)norhomotropane)
VTD58H1Z2X (Dopamine)
تواريخ الأحداث: Date Created: 20150421 Date Completed: 20160315 Latest Revision: 20191210
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC5589077
DOI: 10.1021/acschemneuro.5b00077
PMID: 25891987
قاعدة البيانات: MEDLINE
الوصف
تدمد:1948-7193
DOI:10.1021/acschemneuro.5b00077