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.
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.
Jagerovic
Nadine
N
Instituto de Química Médica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain. nadine@iqm.csic.es
Hernandez-Folgado
Laura
L
Alkorta
Ibon
I
Goya
Pilar
P
Martín
María Isabel
MI
Dannert
María Teresa
MT
Alsasua
Angela
A
Frigola
Jordi
J
Cuberes
María Rosa
MR
Dordal
Alberto
A
Holenz
Jörg
J
D000818:Animals; D001665:Binding Sites; D003511:Cyclohexanols / Q000494:pharmacology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects
D003511:Cyclohexanols; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014230:Triazoles; C017957:1,2,4-triazole-3-carboxamide; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant