Subtle Structural Modification of a Synthetic Cannabinoid Receptor Agonist Drastically Increases its Efficacy at the CB1 Receptor.
Hideaki Yano, Rezvan Chitsazi, Christopher Lucaj, Phuong Tran, Alexander F Hoffman, Michael H Baumann, Carl R Lupica, Lei Shi
Author Information
Hideaki Yano: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States. ORCID
Rezvan Chitsazi: Computational Chemistry and Molecular Biophysics Section, National Institutes of Health, Baltimore, Maryland 21224, United States.
Christopher Lucaj: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States.
Phuong Tran: Computational Chemistry and Molecular Biophysics Section, National Institutes of Health, Baltimore, Maryland 21224, United States.
Alexander F Hoffman: Electrophysiology Research Section, National Institutes of Health, Baltimore, Maryland 21224, United States.
Michael H Baumann: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, United States. ORCID
Carl R Lupica: Electrophysiology Research Section, National Institutes of Health, Baltimore, Maryland 21224, United States.
Lei Shi: Computational Chemistry and Molecular Biophysics Section, National Institutes of Health, Baltimore, Maryland 21224, United States. ORCID
The emergence of synthetic cannabinoid receptor agonists (SCRAs) as illicit psychoactive substances has posed considerable public health risks, including fatalities. Many SCRAs exhibit much higher efficacy and potency compared with the phytocannabinoid Δ-tetrahydrocannabinol (THC) at the cannabinoid receptor 1 (CB1R), leading to dramatic differences in signaling levels that can be toxic. In this study, we investigated the structure-activity relationships of aminoalkylindole SCRAs at CB1Rs, focusing on 5F-pentylindoles containing an amide linker attached to different head moieties. Using in vitro bioluminescence resonance energy transfer assays, we identified a few SCRAs exhibiting significantly higher efficacy in engaging the G protein and recruiting β-arrestin than the reference CB1R full agonist CP55940. Importantly, the extra methyl group on the head moiety of 5F-MDMB-PICA, as compared to that of 5F-MMB-PICA, led to a large increase in efficacy and potency at the CB1R. This pharmacological observation was supported by the functional effects of these SCRAs on glutamate field potentials recorded in hippocampal slices. Molecular modeling and simulations of the CB1R models bound with both of the SCRAs revealed critical structural determinants contributing to the higher efficacy of 5F-MDMB-PICA and how these subtle differences propagated to the receptor-G protein interface. Thus, we find that apparently minor structural changes in the head moiety of SCRAs can cause major changes in efficacy. Our results highlight the need for close monitoring of the structural modifications of newly emerging SCRAs and their potential for toxic drug responses in humans.
