Tricyclic pyrazoles. Part 2: Synthesis and biological evaluation of novel 4,5-dihydro-1H-benzo[g]indazole-based ligands for cannabinoid receptors.
A series of 4,5-dihydro-1H-benzo[g]indazole-3-carboxamides (2a-k) as analogues of the previously reported CB(2) 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 CB(1) and CB(2) 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 CB(2) 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 CB(1) antagonistic activity was highlighted for these compounds.
Murineddu
Gabriele
G
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy.
Ruiu
Stefania
S
Mussinu
Jean-Mario
JM
Loriga
Giovanni
G
Grella
Giuseppe E
GE
Carai
Mauro A M
MA
Lazzari
Paolo
P
Pani
Luca
L
Pinna
Gérard A
GA
D000818:Animals; D063387:Cannabinoid Receptor Antagonists; D005772:Gastrointestinal Transit / Q000187:drug effects / Q000502:physiology; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043882:Receptors, Cannabinoid / Q000378:metabolism; D000077285:Rimonabant; D013329:Structure-Activity Relationship
C503151:4,5-dihydro-1H-benzo(g)indazole; D063387:Cannabinoid Receptor Antagonists; D007191:Indazoles; D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D000077285:Rimonabant