Delta-9-THC and psychoactive derivatives were scrutinized with molecular electrostatic potential (MEP) and ligand-CB1 interaction. At the B3LYP/6-31G** level, MEP maps of the most active cannabinoids (mac), pKi ≥ 6.72 (1-13), revealed that the directional orientation of the lone pair of electrons in the phenolic OH, in general, produces a greater interaction with the substituent at position C9, orienting the carbocyclic ring system, reflecting the psychoactivity of the compounds. In addition, the existence of the side alkyl chain contributes to improving this property. In less active cannabinoids (lac), pKi < 6.72 (14-22), the negative MEP shows a more spread out, “diluted” electron density, probably due to the orientation of the carbocyclic ring system unfavorable to the pharmacophoric conformation. Furthermore, the MEP maps show cannabinoids 14-22 presenting small differences in the distribution of this density, when compared to 1-13, which seems crucial to the decrease in psychoactivity. When examining the ligand-CB1 interaction, the orientations of the compounds were shown to be governed basically by the hydrophobic pockets between helices III, IV, VI, and VII; with the most active alkyl fragment (1-13) directed to the hydrophobic site, the nonpolar fragment (methylcyclohexene) to the hydrophobic pocket, the phenolic OH to the hydrophilic pocket and the oxane fragment oriented to a small hydrophilic pocket of CB1. In the lac (14-22), the poses of the substituents COOH (14), COOCH3 (16), and COCH3 (22) were oriented towards a hydrophobic pocket and 15, 17, 18, and 21 presented the oxygenated groups directed to the hydrophilic sites of the CB1 receptor. The OH substituent in 19 directs it to the hydrophobic pocket and 20, with the OH group but distant from phenolic OH, presents said group also directed to this hydrophobic pocket of CB1. The scrutiny of cannabinoids with MEP and the ligand-CB1 interaction could guide the design of new molecules with better psychoactivity.
Read full abstract