Research on analgesic cannabinoids in light of molecular electrostatic potential and CB1 and CB2 ligand-receptor interaction

Molecular electrostatic potential (MEP) and CB1 and CB2 ligand-receptor interactions are used in the research of eighteen (18) cannabinoids to investigate structural features necessary for analgesia. Calculations were performed using quantum chemical (B3LYP/6-31G**) and molecular mechanics approaches. The MEP maps reflect the occurrence of the pharmacophoric conformation that provides the greatest analgesia in cannabinoids 1 to 7 and 15 to 18 (most active class or MA classe). Furthermore, this conformation is not observed in cannabinoids 8 to 14 (least active class or LA class), indicating their lowest analgesia. Interactions with the CB1 receptor show the alkyl side chain at the C3 position playing a key role in anchoring the ligand to the active site and in hydrophobic interactions with residues VAL196, LEU359, and TRP279. The presence of the phenolic OH group contributes to the stability of the complex through hydrogen bonds with residue SER383 and π-π interactions with residues PHE170 and PHE268. Modifications to the A ring (cyclohexane) affect the orientation of the ligand in the active site, and polar groups favor interactions with residue ILE267. Molecular rigidity, proximity to residue HIS178, and stereochemistry influence analgesia. Interactions with the CB2 receptor show that cannabinoids with CH3 groups at C1' and C2' in the alkyl side chain have greater affinity for this receptor. The formation of multiple hydrophobic interactions and the favorable positioning of the OH group enable affinity in the CB2 receptor active site. Ligands with terminal aromatic rings show high affinity for residues PHE87, PHE183, and TRP194, and the presence of the phenolic OH group results in greater analgesia. The -SH, COOH, and CH₂OH groups promote good stability through hydrogen bonds or salt bridges with residues HIS95 and SER285. The A ring is important for ligand anchoring, with the position and nature of the substituent group at C9 being critical factors in this anchoring. Excessive proximity to residue HIS95 tends to reduce analgesia, while interaction with residue LEU182 favors stability. Additionally, the structural rigidity introduced by double bonds or amine substitutions generally decreases the analgesic activity of cannabinoids. The results obtained may serve as a guide for the design of new cannabinoids with analgesic potential.