morphinans and cyclorphan

Opioid agonists are used clinically for the treatment of acute and chronic pain, however, their clinical use is limited due to the presence of undesired side effects. Dual agonists, simultaneously targeting mu and kappa opioid receptors, show fewer side effects than that of selective agonists. In the present work, 2D- and 3D- Quantitative Structure Activity Relationship studies were performed on a series of aminomorphinan derivatives as dual agonists, using a wide range of descriptors. The aim of the study was to identify the structural requirements for the activity of these compounds towards mu and kappa opioid receptors and using the models, with best external predictability, for predicting the activities of new hits obtained from shape based virtual screening of drug like compounds from ZINC database. Genetic algorithm-based GFA and G/PLS techniques were used to derive the 2D-QSAR models. Common feature-based pharmacophore was used for aligning the compounds for 3D-QSAR. All the models were validated both internally and externally using statistical metrics. The coverage estimation of the models was carried out with applicability domain calculation. Six enriched hits were identified as novel prospective dual agonist based on good Blood Brain Barrier permeability and their activities towards mu and kappa opioid receptors, predicted by the best QSAR models. The known potent dual agonist, cyclorphan, and two highly prospective dual agonists were docked to both the receptors and binding free energies were calculated using MMGBSA. Molecular dynamics studies were performed on the docked complexes with both the receptors to establish stability of the complexes.

Topics: Blood-Brain Barrier; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Morphinans; Multiprotein Complexes; Protein Binding; Quantitative Structure-Activity Relationship; Receptors, Opioid, kappa; Receptors, Opioid, mu

The phenolic group of the potent mu and kappa opioid morphinan agonist/antagonists cyclorphan and butorphan was replaced by phenylamino and benzylamino groups including compounds with para-substituents in the benzene ring. These compounds are highly potent mu and kappa ligands, e.g., p-methoxyphenylaminocyclorphan showing a K(i) of 0.026 nM at the mu receptor and a K(i) of 0.03 nM at the kappa receptor. Phenyl carbamates and phenylureas were synthesized and investigated. Selective o-formylation of butorphan and levorphanol was achieved. This reaction opened the way to a large set of 2-substituted 3-hydroxymorphinans, including 2-hydroxymethyl-, 2-aminomethyl-, and N-substituted 2-aminomethyl-3-hydroxymorphinans. Bivalent ligands bridged in the 2-position were also synthesized and connected with secondary and tertiary aminomethyl groups, amide bonds, and hydroxymethylene groups, respectively. Although most of the 2-substituted morphinans showed considerably lower affinities compared to their parent compounds, the bivalent ligand approach led to significantly higher affinities compared to the univalent 2-substituted morphinans.

Topics: Binding Sites; Ligands; Molecular Conformation; Morphinans; Narcotic Antagonists; Structure-Activity Relationship