Synthesis and nicotinic acetylcholine receptor in vitro and in vivo pharmacological properties of 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogues of 2′-fluoro-3′-(4- nitrophenyl)deschloroepibatidine

Pauline Ondachi, Ana Castro, Charles W Luetje, M. Imad Damaj, S. Wayne Mascarella, Hernán A. Navarro, F. Ivy Carroll

Research output: Contribution to journalArticle

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Abstract

Herein, we report the synthesis and nicotinic acetylcholine receptor (nAChR) in vitro and in vivo pharmacological properties of 2′-fluoro- 3′-(substituted phenyl)deschloroepibatidines 5b-g, analogues of 3′-(4-nitrophenyl) compound 5a. All compounds had high affinity for α4β2-nAChR and low affinity for α7-nAChR. Initial electrophysiological studies showed that all analogues were antagonists at α4β2-, α3β4-, and α7-nAChRs. The 4-carbamoylphenyl analogue 5g was highly selective for α4β2-nAChR over α3β4- and α7-nAChRs. All the analogues were antagonists of nicotine-induced antinociception in the tail-flick test. Molecular modeling docking studies using the agonist-bound form of the X-ray crystal structure of the acetylcholine binding protein suggested several different binding modes for epibatidine, varenicline, and 5a-g. In particular, a unique binding mode for 5g was suggested by these docking simulations. The high binding affinity, in vitro efficacy, and selectivity of 5g for α4β2-nAChR combined with its nAChR functional antagonist properties suggest that 5g will be a valuable pharmacological tool for studying the nAChR and may have potential as a pharmacotherapy for addiction and other central nervous system disorders.

Original languageEnglish
Pages (from-to)6512-6522
Number of pages11
JournalJournal of Medicinal Chemistry
Volume55
Issue number14
DOIs
StatePublished - Jul 26 2012

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Nicotinic Receptors
Pharmacology
epibatidine
Central Nervous System Diseases
2-fluoro-3-(4-nitrophenyl)deschloroepibatidine
In Vitro Techniques
deschloroepibatidine
Nicotine
Acetylcholine
Carrier Proteins
X-Rays
Drug Therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and nicotinic acetylcholine receptor in vitro and in vivo pharmacological properties of 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogues of 2′-fluoro-3′-(4- nitrophenyl)deschloroepibatidine. / Ondachi, Pauline; Castro, Ana; Luetje, Charles W; Damaj, M. Imad; Mascarella, S. Wayne; Navarro, Hernán A.; Carroll, F. Ivy.

In: Journal of Medicinal Chemistry, Vol. 55, No. 14, 26.07.2012, p. 6512-6522.

Research output: Contribution to journalArticle

Ondachi, Pauline ; Castro, Ana ; Luetje, Charles W ; Damaj, M. Imad ; Mascarella, S. Wayne ; Navarro, Hernán A. ; Carroll, F. Ivy. / Synthesis and nicotinic acetylcholine receptor in vitro and in vivo pharmacological properties of 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogues of 2′-fluoro-3′-(4- nitrophenyl)deschloroepibatidine. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 14. pp. 6512-6522.
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