Date of Award
Trudell, Mark L.
This study was aimed at the development of novel CB1 cannabinoid receptor antagonists that may have clinical applications for the treatment of cannabinoid and psychostimulant addiction. The rationale for the design for our target was to incorporate a bioisosteric 1,2,3-triazole ring into the vicinal diaryl group revealed in the prototypical antagonist/inverse agonist SR141716 (Rimonabant) that was presumed to interact with a unique region in the CB1 receptors. Based on our preliminary results we identified a novel series of 1,2,3-triazole ester and keto derivatives as lead compounds for biological evaluation. Here in the design rationale, synthesis and CB1 receptor affinity for a series of 4,5-diaryl-1-substituted-1,2,3-triazoles of ester and ketones is described. These derivatives were synthesized via a one-pot regiospecific click/acylation reaction sequence from 1-azido-2,4-dichlorobenzene and commercially available arylacetylenes. From the structure-activity studies the 5-(4-chlorophenyl) congeners exhibited the most potent CB1 receptor affinities relative to other 5-(substituted-phenyl) moieties. The 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-propylcarbonyl-1,2,3-triazole (31a) was found to be the most potent (Ki = 4.6 nM) CB1 receptor ligand of the series and exhibited high CB1 selectivity (CB2/CB1 = 417).
The triazole ester 31a was further characterized as a cannabinoid antagonist in locomotor-activity studies by blocking the locomotor-reducing effects of cannabinoid agonist WIN55,212-2. In addition, unlike the prototypical cannabinoid antagonist SR141716A (Rimonabant), the triazole ester 31a did not exhibit increased activity in locomotor activity studies, thus indicating the potential for a neutral antagonist profile.
Verma, Abha, "Design, Synthesis and Biological Evaluation of Novel Cannabinoid Antagonist" (2012). University of New Orleans Theses and Dissertations. 1527.