In vitro metabolism of diarylpyrazoles, a novel group of cannabinoid receptor ligands.
Diarylpyrazoles are a group of 1,5-diphenylpyrazole analogs of which several have been found to exhibit antagonist properties toward the cannabinoid receptors. SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], the first reported antagonist, is a highly potent and selective CB1 receptor ligand that prevents or reverses CB1-mediated effects. Other analogs, such as AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] and AM281 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide], have also shown high binding affinities to the central cannabinoid receptor and behave as antagonists/inverse agonists. There has been no report on the metabolism of any of the diarylpyrazoles, and it is unknown whether their metabolites retain any receptor binding properties. We report a study of the in vitro metabolisms of three diarylpyrazole analogs, SR141716A, AM251, and AM281, in rat liver microsomes. The metabolic profile was obtained using high-performance liquid chromatography with UV and mass spectrometry detectors. All identified metabolites are characterized by structural modifications on the terminal group of the 3-substituent. Thus, three pairs of isomeric metabolites were identified from the microsomal incubation of SR141716A; these metabolites are products of hydroxylation, hydroxylation followed by dehydration, and a combination of the two. For AM251, only four metabolic products were detected, with two resulting from monohydroxylation of the piperidine ring and the other two being products of dehydration of the first pair of metabolites. For AM281, in which the terminal group of the 3-substituent is a morpholine ring, dehydration of the first two metabolites yielded a single third metabolite due to only one possible position for the carbon-carbon double bond on the morpholinyl ring.
Zhang
Qiang
Q
Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
Ma
Peng
P
Wang
Weiqun
W
Cole
Richard B
RB
Wang
Guangdi
G
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines / Q000378:metabolism*; D010880:Piperidines / Q000378:metabolism*; D011720:Pyrazoles / Q000378:metabolism*; D051381:Rats; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D000077285:Rimonabant
D009025:Morpholines; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C103505:AM 251; D000077285:Rimonabant; C109925:AM 281