title: Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile.
abstract: New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB(1) receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB(1) receptor, with K(i) concentrations comparable to the reference compounds 1, 4 and 5, and exhibited CB(1) selectivity comparable to 1 and 2. Docking experiments and molecular dynamics (MD) simulations explained the potent hCB(1) binding affinity of compounds 31 and 37. According to our previous studies, 31 and 37 formed a H-bond with K3.28(192), which accounted for the high affinity for the receptor inactive state and the inverse agonist activity. The finding of inhibition of food intake following their acute administration to rats, supported the concept that the CB(1) selective compounds 4 and 52 act as antagonists/inverse agonists.
authors: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy. romano.silvestri@uniroma1.it
authors: Romano
authors: R
authors: Silvestri
authors: Alessia
authors: A
authors: Ligresti
authors: Giuseppe
authors: G
authors: La Regina
authors: Francesco
authors: F
authors: Piscitelli
authors: Valerio
authors: V
authors: Gatti
authors: Antonella
authors: A
authors: Brizzi
authors: Serena
authors: S
authors: Pasquini
authors: Antonio
authors: A
authors: Lavecchia
authors: Marco
authors: M
authors: Allarà
authors: Noemi
authors: N
authors: Fantini
authors: Mauro Antonio Maria
authors: MA
authors: Carai
authors: Ettore
authors: E
authors: Novellino
authors: Giancarlo
authors: G
authors: Colombo
authors: Vincenzo
authors: V
authors: Di Marzo
authors: Federico
authors: F
authors: Corelli
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D011485:Protein Binding; D011758:Pyrroles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism
chemical_list: D008024:Ligands; D011758:Pyrroles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2