2022 Annual Meeting
(585f) Comparison of Dissociation Kinetics and Mechanism of Classical and Non-Classical Cannabinoids from Cannabinoid Receptors
Cannabinoid receptors (CBs) are part of the endocannabinoid signaling system, which help to maintain homeostasis in neuron signaling to control pain, obesity, and other neurological disorders. Therefore, synthetic cannabinoids (SCs) are designed and tested to target CBs as potential therapeutical selective drugs. Initially, SCs were designed by modulating the scaffolds of known phytocannabinoids. However, recent efforts have led to the rapid discovery of chemically diverse synthetic cannabinoids (Novel Psychoactive Substance; NPS), which have a high affinity towards CBs and significantly modulate the receptor activities. These molecules were started to get sold in the market as abusive drugs under different brand names (e.g., K2, spice) and caused thousands of hospitalizations of patients across the US due to more adverse effects, including impairment of fine motor skills and increased blood pressure, tachycardia. It is hypothesized that β-arrestin biased downstream signaling of these NPSs causes more adversarial effects compared to classical cannabinoids. How these classical and non-classical cannabinoids affect receptor conformational dynamics distinctly, has not been mechanistically studied. In this project, we compare the unbinding mechanism and kinetics of a non-classical cannabinoid, MDMB-Fubinaca, and a classical cannabinoid, HU-210, using biased and unbiased simulation. We implement transition-based reweighting analysis method (TRAM) to obtain unbiased thermodynamics and kinetics from the multi ensemble simulation data. This study provides a mechanistic understanding of biased signaling of non-classical cannabinoids.