1. Tricyclic pyrazoles. Part 2: Synthesis and biological evaluation of novel 4,5-dihydro-1H-benzo[g]indazole-based ligands for cannabinoid receptors
- Author
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Giovanni Loriga, Luca Pani, Paolo Lazzari, Stefania Ruiu, Gérard Aimé Pinna, Gabriele Murineddu, Giuseppe Enrico Grella, Mauro A.M. Carai, and Jean-Mario Mussinu
- Subjects
Agonist ,Cannabinoid receptor ,Indazoles ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Ligands ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Piperidines ,Drug Discovery ,medicine ,Animals ,Receptor ,Gastrointestinal Transit ,Receptors, Cannabinoid ,Molecular Biology ,Cannabinoid Receptor Antagonists ,1-(2′,4′- Dichlorophenyl)-7-iodo-N-piperidin-1-yl-4,5-dihydro-1H-benzo[g] indazole-3-carboxamide ,4,5-Dihydro-1H-benzo[g]indazoles ,Cannabinoids ,Selective CB ,1 ,receptor ligands ,Indazole ,Mice, Inbred ICR ,Molecular Structure ,Ligand ,Organic Chemistry ,Biological activity ,chemistry ,Molecular Medicine ,Pyrazoles ,Rimonabant - Abstract
A series of 4,5-dihydro-1 H -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.
- Published
- 2004