Synthesis, cannabinoid receptor affinity, and molecular modeling studies of substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides.
The new 1-phenyl-5-(1 H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB 1 and hCB 2 receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB 1. On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB 2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB 1 receptor ( K i (CB 2)/ K i (CB 1) = 140.7). Derivative 30, the most potent hCB 1 ligand ( K i = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC 50 approximately 1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.
Silvestri
Romano
R
Dipartimento di Studi Farmaceutici, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Piazzale Aldo Moro 5, Rome, Italy. romano.silvestri@uniroma1.it
Cascio
Maria Grazia
MG
La Regina
Giuseppe
G
Piscitelli
Francesco
F
Lavecchia
Antonio
A
Brizzi
Antonella
A
Pasquini
Serena
S
Botta
Maurizio
M
Novellino
Ettore
E
Di Marzo
Vincenzo
V
Corelli
Federico
F
D001667:Binding, Competitive; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects*; D011994:Recombinant Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship
D008024:Ligands; D011720:Pyrazoles; D011758:Pyrroles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011994:Recombinant Proteins