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.
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.
Silvestri
Romano
R
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
Ligresti
Alessia
A
La Regina
Giuseppe
G
Piscitelli
Francesco
F
Gatti
Valerio
V
Brizzi
Antonella
A
Pasquini
Serena
S
Lavecchia
Antonio
A
Allarà
Marco
M
Fantini
Noemi
N
Carai
Mauro Antonio Maria
MA
Novellino
Ettore
E
Colombo
Giancarlo
G
Di Marzo
Vincenzo
V
Corelli
Federico
F
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
D008024:Ligands; D011758:Pyrroles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2