Synthesis, Nicotinic Acetylcholine Binding, and in Vitro and in Vivo Pharmacological Properties of 2′-Fluoro-(carbamoylpyridinyl)deschloroepibatidine Analogues

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 [3H]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 64raquo;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.

Original languageEnglish (US)
Pages (from-to)1004-1012
Number of pages9
JournalACS Chemical Neuroscience
Volume7
Issue number7
DOIs
StatePublished - Jul 20 2016

Keywords

  • Nicotinic receptors
  • epibatidine analogues
  • in vitro/in vivo studies
  • nAChRs

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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