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Sawaqed – 3D Modeling of ZCZ011 at CB1 Receptors and Applications in Experimental Neuroscience.

 

3D Modeling of ZCZ011 at CB1 Receptors and Applications in Experimental Neuroscience. (2024)

Undergraduates: Laith Sawaqed, Aidan Nance, Zahria Sanders, Pranay Tewari


Faculty Advisor: Rachel Penton
Department: Psychology and Neuroscience

Cannabinoid Receptors Type I (CB1Rs) are Gi-protein coupled receptors that play key modulatory roles during synaptic plasticity and homeostatic processes in the brain. These receptors are composed of 7 transmembrane alpha-helices and 1 C-terminus intracellular helix. ZCZ011 is a novel drug that acts as an allosteric agonist in CB1R cAMP pathways but as a PAM in pERK activation and β-arrestin recruitment. The binding site of ZCZ011 is an extra helical site on the upper half of TMH 2-3-4 at a distance of 7.9 Å from the orthosteric site. In this study, we modeled the activation of CB1Rs by ZCZ011, depicting the displacement of TMH6 and TMH2 as critical steps necessary for CB1R activation. This novel drug enhances the activation of CB1Rs through stabilizing the active state and promoting the rearrangement of TMH2. Potential applications of the ZCZ011 compound involve treatment of opioid use disorder, nociception, and other inflammatory CNS disorders.