Structural-activity relationship study on C-4 carbon atom of the CB1 antagonist SR141716 : synthesis and pharmacological evaluation of 1,2,4-triazole-3-carboxamides

• Published in: European journal of medicinal chemistry Vol. 41; no. 1; pp. 114 - 120
• Main Authors: JAGEROVIC, Nadine, HERNANDEZ-FOLGADO, Laura, HOLENZ, Jörg, ALKORTA, Ibon, GOYA, Pilar, MARTIN, Maria Isabel, DANNERT, Maria Teresa, ALSASUA, Angela, FRIGOLA, Jordi, CUBERES, Maria Rosa, DORDAL, Alberto
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 2006
• Subjects: Animals; Binding Sites; Biological and medical sciences; Cyclohexanols - pharmacology; Male; Medical sciences; Mice; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperidines - pharmacology; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Vas Deferens - drug effects; Organic hydrazide; CB1 cannabinoid receptor; 1,2,4-Triazole; Five membered ring; Nitrogen heterocycle; Rodentia; Benzene derivatives; In vitro; Modeling; Vas deferens; Vertebrata; Mammalia; Structure activity relation; Mouse; Chlorine Organic compounds; Animal; Canal déférent de souris; Molecular model; Affinity; Carboxamide; Antagonist; Cannabiroide; Chemical synthesis; SR141716
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2005.06.012

A series of 1,2,4-triazole-3-carboxamides has been prepared from alkyl-1,2,4-triazole-3-carboxylates under mild conditions. The ability of these triazoles to displace [3H]-CP55940 from CB1 cannabinoid receptor was measured. However, they showed only poor to moderate binding affinities, indicating that substitution of the C-4 pyrazole atom of the CB1 reference compound SR141716 by a nitrogen atom results in loss of affinity. Further investigations for functionality indicated that the compound 6a exhibited significant cannabinoid antagonistic properties in the mouse vas deferens functional assay. This leads us to the conclusion that 6a binds at a different CB1 binding site or at a new cannabinoid receptor subtype.