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 journalArticle

3 Citations (Scopus)

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

Fingerprint

epibatidine
Nicotine
Inhibitory Concentration 50
Acetylcholine
Tail
Assays
Pharmacology
Dopamine
In Vitro Techniques
deschloroepibatidine
Lead

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

Cite this

Synthesis, Nicotinic Acetylcholine Binding, and in Vitro and in Vivo Pharmacological Properties of 2′-Fluoro-(carbamoylpyridinyl)deschloroepibatidine Analogues. / Ondachi, Pauline W.; Castro, Ana H.; Luetje, Charles W; Wageman, Charles R.; Marks, Michael J.; Damaj, M. Imad; Mascarella, S. Wayne; Navarro, Hernán A.; Carroll, F. Ivy.

In: ACS Chemical Neuroscience, Vol. 7, No. 7, 20.07.2016, p. 1004-1012.

Research output: Contribution to journalArticle

Ondachi, PW, Castro, AH, Luetje, CW, Wageman, CR, Marks, MJ, Damaj, MI, Mascarella, SW, Navarro, HA & Carroll, FI 2016, 'Synthesis, Nicotinic Acetylcholine Binding, and in Vitro and in Vivo Pharmacological Properties of 2′-Fluoro-(carbamoylpyridinyl)deschloroepibatidine Analogues', ACS Chemical Neuroscience, vol. 7, no. 7, pp. 1004-1012. https://doi.org/10.1021/acschemneuro.6b00107
Ondachi, Pauline W. ; Castro, Ana H. ; Luetje, Charles W ; Wageman, Charles R. ; Marks, Michael J. ; Damaj, M. Imad ; Mascarella, S. Wayne ; Navarro, Hernán A. ; Carroll, F. Ivy. / Synthesis, Nicotinic Acetylcholine Binding, and in Vitro and in Vivo Pharmacological Properties of 2′-Fluoro-(carbamoylpyridinyl)deschloroepibatidine Analogues. In: ACS Chemical Neuroscience. 2016 ; Vol. 7, No. 7. pp. 1004-1012.
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AU - Castro, Ana H.

AU - Luetje, Charles W

AU - Wageman, Charles R.

AU - Marks, Michael J.

AU - Damaj, M. Imad

AU - Mascarella, S. Wayne

AU - Navarro, Hernán A.

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