title: Synthesis, nicotinic acetylcholine receptor binding, in vitro and in vivo pharmacology properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs.
abstract: Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine (4) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs (5a-e and 6a-e). All of the analogs had high binding affinity for α4β2(∗)-nAChRs. Several of the analogs were potent antagonists of α4β2-nAChRs in in vitro efficacy tests and were potent antagonists of nicotine-induced antinociception in the mouse tail-flick test. Compound 6b had a Ki = 0.13 nM in the binding assay, 25- and 46-fold selectivity for the α4β2(∗)-nAChR relative to the α3β4- and α7-nAChR, respectively, in the in vitro efficacy test and an AD50 = 0.13 μg/kg in the tail-flick test. Combined with favorable calculated physiochemical properties compared to varenicline, our findings suggest that 6b should be considered for development as a potential pharmacotherapy for treating nicotine addiction and other CNS disorders.
authors.affiliation: Center for Drug Discovery, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: Pauline W
authors.initials: PW
authors.lastname: Ondachi
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33101, United States.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 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, FL 33101, United States.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Luetje
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Campus, PO Box 980615, Richmond, VA 23298, United States.
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
authors.affiliation: Center for Drug Discovery, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.affiliation: Center for Drug Discovery, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.affiliation: Center for Drug Discovery, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States. Electronic address: fic@rti.org.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D013329:Structure-Activity Relationship; D014026:Nicotiana / Q000737:chemistry*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D011725:Pyridines; D011978:Receptors, Nicotinic; C507197:deschloroepibatidine
keywords: Epibatidine analogs; In vitro/in vivo study; Nicotine receptor; Varenicline; nAChR antagonist