Design, Synthesis and Biological Evaluation of Novel Cannabinoid Antagonist

<p>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 (<strong>­31a</strong>) was found to be the most potent (<em>K</em>_i = 4.6 nM) CB1 receptor ligand of the series and exhibited high CB1 selectivity (CB2/CB1 = 417).</p> <p>The triazole ester <strong>31a</strong> 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 <strong>SR141716A</strong> (Rimonabant), the triazole ester <strong>31a</strong> did not exhibit increased activity in locomotor activ­ity studies, thus indicating the potential for a neutral antagonist profile.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation-Restricted

Discipline thesis:degree_discipline

Chemistry

Year

2012

Author dc:creator

• Verma, Abha

Contributors dc:contributor

• Trudell, Mark L.

• Cannabinoids
• CB1-antagonist
• Drug abuse therapeutics
• Rimonabant
• 1,2,3-triazoles
• Click reactions
• Medicinal and Pharmaceutical Chemistry

Repository record dc:identifier

https://scholarworks.uno.edu/td/1527

OAI identifier oai:identifier

oai:scholarworks.uno.edu:td-2528