Tricyclic pyrazoles. Part 2: Synthesis and biological evaluation of novel 4,5-dihydro-1H-benzo[g]indazole-based ligands for cannabinoid receptors

Abstract

A series of 4,5-dihydro-1H-benzo[g]indazole-3-carboxamides (2a-k) as analogues of the previously reported CB2 ligands 6-chloro- and 6-methyl-1-(2′,4′-dichlorophenyl)-N-piperidin-1-yl-1, 4-dihydroindeno[1,2-c]pyrazole-3-carboxamides (1a,b) was synthesized and their affinity and selectivity towards CB1 and CB2 receptors were evaluated. Several of the new compounds (2a,b,c,d and i) exhibited CB 1 affinity in the nanomolar range with moderate or negligible affinity towards CB2 receptors. Compounds 2a and c increased intestinal propulsion in mouse. Their pro-kinetic effects were reversed by the reference CB agonist CP-55,940. Consequently, in vivo CB1 antagonistic activity was highlighted for these compounds. © 2005 Elsevier Ltd. All rights reserved.