Establishment of kappa opioid receptor agonists pharmacophore with molecular modeling method.

AIM: To build up nonpeptide kappa-opioid receptor agonists pharmacophore. METHODS: Five structurally diverse, highly active nonpeptide kappa-opioid agonists were retrieved from MDL MDDR database. Molecular mechanics method were used to seek out 50 lower energy conformations for each compound. Taking nitrogen atom of pyrrolidine and acyl acetamide as overlay points, 5 agonists were superimposed to each other with their most favorite conformation. From the overlay map, the structure specificity of nonpeptide kappa-opioid receptor agonists were elucidated. RESULTS: According to this pharmacophore, the pyrrolidine ring, the carbonyl group of acyl acetamide, and the hydrophobic group attached to acyl acetamide were suggested to be the structure-specific moieties of kappa-opioid agonists. Moreover, by comparing kappa 1-opioid receptor sequence of mouse with other G-protein-coupled receptors, we determined those conserve residues existing on transmembrane regions which might interact with the suggested groups. The carboxyl of Asp138 might interact with N atom of pyrrolidine by forming a hydrogen bond. The hydroxyl of Ser187 and the carbonyl group of kappa-opioid agonists might form another hydrogen bond, which was critical for its kappa selective affinity. The hydrophobic group attached to acyl acetamide might have hydrophobic interaction with aromatic residues of kappa-opioid receptors. CONCLUSION: These kappa agonists pharmacophore were helpful to select specific positions in the lead compounds to be occupied by hydrophobic moieties to limit their ability to across the blood-brain barrier.