title: Synthesis and structure-activity relationships (SARs) of 1,5-diarylpyrazole cannabinoid type-1 (CB(1)) receptor ligands for potential use in molecular imaging.
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 GTPgamma(35)S-binding assay. clog 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 clog Ps from 3.61 to 6.25. An interesting new ligand, namely N-(piperidin-1-yl)-1-(2-bromophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxamide (9j), emerged from the synthesized set with appealing properties (K(B)=11 nM; CB(1) selectivity>773; clog 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).
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. donohues@intra.nimh.nih.gov
authors.forename: Sean R
authors.initials: SR
authors.lastname: Donohue
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D015195:Drug Design; D006801:Humans; D021621:Imaging, Three-Dimensional; D008024:Ligands; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1