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

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 CB 1 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. © 2005 Elsevier SAS. All rights reserved.Peer Reviewe

Discovery of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole, a novel in vivo cannabinoid antagonist containing a 1,2,4-triazole motif

A new series of 1,2,4-triazoles have been prepared and the evaluation of their cannabinoid properties have been carried out. Compound 8 showed cannabinoid silent antagonist activity in mouse vas deferens and guinea pig ileum preparations and in vivo assays (cannabinoid tetrad) in mouse. It did not have intrinsic activity in these bioassays, and therefore, it did not behave as a partial agonist or an inverse agonistThis work was supported by Spanish Grant SAF 00-0114-C02. L.H.-F. is recipient of the I3P Fellowship from the C.S.I.C. Laboratorios Dr. Esteve, S.A. is gratefully acknowledged. L.H.-F. thanks the Spanish Society of Therapeutic Chemistry (SEQT) for the Ramon Madroñero Young Researcher Award.Peer reviewe