Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1H-pyrrol-1- yl)-1H-pyrazole-3-carboxamides as cannabinoid receptor ligands

Abstract A series of N -alkyl 1-aryl-5-(1 H -pyrrol-1-yl)-1 H -pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB 1 . n -Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert -alkyl chain at the 3-carboxamide nitrogen showed greater hCB 1 receptor affinity than the corresponding unbranched compounds. In particular, the tert -butyl group as a chain terminal moiety strongly improved hCB 1 receptor affinity (compound 24 : K i  = 45.6 nM; 29 : K i  = 37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB 1 ligands.