Identification of structural factors that affect binding to cannabinoid receptor type 1

Abstract

Similar to the opioid system, the endocannabinoid system which regulates immune response, memory and nociceptive thresholds, cell communication, appetite, and metabolism, also modulates (via Cannabinoid receptor type 1 - CB1R) the rewarding effects of natural and synthetic cannabinoids. Although currently there is significant controversy concerning the (legal) use of cannabis, it has been established that prolonged consumption of a large variety of chemicals from the cannabinoid family can lead to the development of psychiatric and cardiovascular pathologies. In addition to (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC or simply THC), the main addictive component of cannabis, 43 other synthetic cannabimimetic agents are currently classified as Schedule I drugs and their use in the U.S. is illegal (DEA-DCT-DIR-032-18 [1]). In this study, three-dimensional spectrometric data-activity relationship (3D-SDAR) quantitative and categorical models aimed at better understanding the molecular mechanism of action and the structural features governing binding to CB1R were developed. The performance parameters for a consensus model constructed from composite PLS and KNN quantitative models achieved R2 of 0.703 for an external blind set and an accuracy of 0.846, sensitivity of 0.870, and specificity of 0.840 for binary classification. In addition to the classical A, B, C-tricyclic terpenoid system, other structural alerts were also discovered and reported. We also identified the presence of a hERG linked toxicophore in the molecular structures of a subset of diaryl-(piperidinyl)purines which are known to be selective and potent CB1R binders.