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Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor
The
cannabinoid 1 receptor (CB1R) is one of the most widely expressed
metabotropic G protein-coupled receptors in brain, and its participation
in various (patho)Âphysiological processes has made CB1R activation
a viable therapeutic modality. Adverse psychotropic effects limit
the clinical utility of CB1R orthosteric agonists and have promoted
the search for CB1R positive allosteric modulators (PAMs) with the
promise of improved drug-like pharmacology and enhanced safety over
typical CB1R agonists. In this study, we describe the synthesis and <i>in vitro</i> and <i>ex vivo</i> pharmacology of the
novel allosteric CB1R modulator GAT211 (racemic) and its resolved
enantiomers, GAT228 (<i>R</i>) and GAT229 (<i>S</i>). GAT211 engages CB1R allosteric site(s), enhances the binding of
the orthosteric full agonist [<sup>3</sup>H]ÂCP55,490, and reduces
the binding of the orthosteric antagonist/inverse agonist [<sup>3</sup>H]ÂSR141716A. GAT211 displayed both PAM and agonist activity in HEK293A
and Neuro2a cells expressing human recombinant CB1R (hCB1R) and in
mouse-brain membranes rich in native CB1R. GAT211 also exhibited a
strong PAM effect in isolated vas deferens endogenously expressing
CB1R. Each resolved and crystallized GAT211 enantiomer showed a markedly
distinctive pharmacology as a CB1R allosteric modulator. In all biological
systems examined, GAT211’s allosteric agonist activity resided
with the <i>R-</i>(+)-enantiomer (GAT228), whereas its PAM
activity resided with the <i>S</i>-(−)-enantiomer
(GAT229), which lacked intrinsic activity. These results constitute
the first demonstration of enantiomer-selective CB1R positive allosteric
modulation and set a precedent whereby enantiomeric resolution can
decisively define the molecular pharmacology of a CB1R allosteric
ligand