Abstract
Cannabinoid type-1 (CB 1) receptor ligands, derived from the 1,5-diarylpyrazole core template of rimonabant (Acomplia ®), have been the focus of several studies aimed at examining structure–activity relationships (SARs). The purpose of this study was to design and synthesize a set of compounds based on the 1,5-diarylpyrazole template while focusing on the potential for discovery of CB 1 receptor radioligands that might be used as probes with in vivo molecular imaging. Each synthesized ligand was evaluated for potency as an antagonist at CB 1 and cannabinoid type-2 (CB 2) receptors in vitro using a GTPγ 35S-binding assay. c log P values were calculated with Pallas 3.0. The antagonist binding affinities ( K B) at CB 1 receptors ranged from 11 to >16,000 nM, CB 1 versus CB 2 selectivities from 0.6 to 773, and c log Ps from 3.61 to 6.25. An interesting new ligand, namely N-(piperidin-1-yl)-1-(2-bromophenyl)-5-(4-methoxyphenyl)-4-methyl-1 H-pyrazole-3-carboxamide ( 9j), emerged from the synthesized set with appealing properties ( K B = 11 nM; CB 1 selectivity > 773; c log P = 5.85), for labeling with carbon-11 and development as a radioligand for imaging brain CB 1 receptors in vivo with positron emission tomography (PET).
Published Version
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