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-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB₁ and hCB₂ 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 hCB₂ selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB₁ receptor (K_i (CB ₂)/K_i (CB₁) = 140.7). Derivative 30, the most potent hCB₁ ligand (K_i = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC₅₀ ∼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.