Computational study of RTI - 371, a positive allosteric modulator of the cannabinoid CB1 receptor

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Michael D. Foster (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Patricia Reggio

Abstract: It is now recognized that many G-protein-coupled receptors (GPCRs) contain allosteric binding sites for endogenous and/or synthetic ligands, which are topographically distinct from the agonist-binding site, which is known as the orthosteric site. In contrast to the direct effects on receptor function that are mediated by orthosteric ligands, allosteric drugs act by modulating receptor activity through conformational changes in the receptor that are transmitted from the allosteric to the orthosteric site and/or to effector coupling sites. 3â-(4-methylphenyl)-2â-[3-(4-chlorophenyl)isoxazol-5-yl]tropane (RTI-371) has been shown to be a positive allosteric modulator of human cannabinoid receptor type 1 (CB1). RTI-371 increases the affinity of traditional cannabinoid agonist, CP55,940 and boosts its efficacy. These effects suggest that this compound may cause a structural change in the CB1 receptor, such that the intrinsic activity of CP55,940 is enhanced, perhaps by stabilizing the active conformation of the receptor. RTI-371 has also been reported to be devoid of activity in the absence of agonist, making RTI-371 neither an agonist nor an antagonist at CB1 when applied alone. The goal of this thesis project was to understand the action of RTI - 371 at the molecular level. To this end, five specific aims were pursued. First, a complete Jaguar conformational analysis of RTI-371 was accomplished, establishing both the minimum energy conformations and the global minimum energy conformation of RTI-371. Second, to identify the binding site of RTI-371 at CB1, the forced-biased Metropolis Monte Carlo simulated annealing program (MMC) was employed. Third, because an increase in CP55,940 affinity could be achieved by receptor exit route blockade, the program CAVER was used to identify all exit routes and the most likely exit route for CP55,940 from CB1. Fourth, the results of MMC and CAVER were used to identify the most likely binding site region for RTI-371 at CB1. Fifth, binding sites for RTI-371 in this region of the receptor were explored using an automated docking program Glide. The most favorable binding site identified for RTI-371 at CB1 is consistent with the reported pharmacology of RTI-371, i.e., its ability to boost CP55,940 affinity and efficacy through stabilizing the active state of CB1 receptor.

Additional Information

Language: English
Date: 2011
G proteins $x Receptors $x Research $x Methodology
Cannabinoids $x Receptors $x Research $x Methodology
Allosteric regulation $x Research $x Methodology

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