title: Synthesis, Nicotinic Acetylcholine Binding, and in Vitro and in Vivo Pharmacological Properties of 2'-Fluoro-(carbamoylpyridinyl)deschloroepibatidine Analogues.
abstract: In this study, we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 2'-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues (5, 6a,b, and 7a,b), which are analogues of our lead structure epibatidine. All of the analogues had subnanomolar binding affinity for α4β2*-nAChRs, and all were potent antagonists of α4β2-nAChRs in an in vitro functional assay. Analogues 6a,b were also highly selective for α4β2- relative to α3β4- and α7-nAChRs. Surprisingly, all of the analogues were exceptionally potent antagonists of nicotine-induced antinociception in the mouse tail-flick test, relative to standard nAChR antagonists such as DHβE. 2'-Fluoro-(4-carbamoyl-3-pyridinyl)deschloroepitabidine (6a) displayed an attractive combination of properties, including subnanomolar binding affinity (Ki = 0.07 nM), submicromolar inhibition of α4β2-nAChRs in the functional assay (IC50 = 0.46 μM) with a high degree of selectivity for α4β2- relative to the α3β4/α7-nAChRs (54-/348-fold, respectively), potent inhibition of [(3)H]dopamine release mediated by α4β2*- and α6β2*-nAChRs in a synaptosomal preparation (IC50 = 21 and 32 nM, respectively), and an AD50 of 0.007 μg/kg as an antagonist of nicotine induced antinociception in the mouse tail-flick test which is 64 250 times more potent than DHβE. These data suggest that compound 6a will be highly useful as a pharmacological tool for studying nAChRs and merits further development.
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709, 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, 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.forename: Charles R
authors.initials: CR
authors.lastname: Wageman
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: M Imad
authors.initials: MI
authors.lastname: Damaj
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: 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: F Ivy
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009538:Nicotine / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014316:Tritium / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018678:Cholinergic Agents; D011725:Pyridines; D011978:Receptors, Nicotinic; C507197:deschloroepibatidine; D014316:Tritium; D009538:Nicotine; D004298:Dopamine
keywords: Nicotinic receptors; epibatidine analogues; in vitro/in vivo studies; nAChRs