Premium
KK‐92A, a novel GABA B receptor positive modulator, attenuates the rewarding effects of nicotine in rats (661.9)
Author(s) -
Li Xia,
Kaczanowska Katarzyna,
Sturchler Emmanuel,
Cameron Michael,
McDonald Patricia,
Finn M. G.,
Griffin Patrick,
Markou Athina
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.661.9
Subject(s) - pharmacology , nicotine , in vivo , allosteric modulator , chemistry , agonist , alkaloid , receptor , pharmacokinetics , allosteric regulation , drug , medicine , biology , biochemistry , stereochemistry , microbiology and biotechnology
GABA B receptors (GABA B R) are thought to be one of the most promising targets for the treatment of drug dependence. GABA B R positive allosteric modulators (PAMs) have been shown to exhibit similar effects as agonists in animal models of nicotine dependence with superior side‐effect profiles. This study involved the synthesis of new selective GABA B R PAMs, and the assessment of their effects in animal models of nicotine dependence. New derivatives of BHF177, a potent GABA B R PAM with efficacy in animal models of nicotine dependence, were synthesized. Nine active molecules were selected based on in vitro microsomal stability and efficacy in multiple cell‐based functional assays, including cAMP accumulation, Ca 2+ mobilization, ERK activation and a cellular impedance‐based (CellKey) assay. Among these compounds, KK‐92A showed improved efficacy in the cAMP and Cellkey assays compared to BHF177, and had a similar in vivo drug metabolism and pharmacokinetic profile, thus, was selected for in vivo assessment. We found that KK‐92A decreased intravenous nicotine self‐administration under fixed‐ and progressive‐ratio schedules of reinforcement in rats. The results indicate that KK‐92A, a novel selective GABA B R PAM, inhibited both the primary reinforcing and incentive motivational effects of nicotine, suggesting that GABA B R PAMs may be useful antismoking medications. Grant Funding Source : NIH 2U19DA026838