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)­physiological 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 [³H]­CP55,490, and reduces the binding of the orthosteric antagonist/inverse agonist [³H]­SR141716A. 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

Discovery of the Potent and Selective M1 PAM-Agonist <i>N</i>‑[(3<i>R</i>,4<i>S</i>)‑3-Hydroxytetrahydro‑2<i>H</i>‑pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]­pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects

It is hypothesized that selective muscarinic M₁ subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer’s disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M₁ with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M₁ activation. This manuscript describes the development of a series of M₁-selective pyridone and pyridine amides and their key pharmacophores. Compound <b>38</b> (PF-06767832) is a high quality M₁ selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M₂/M₃ subtype activity, compound <b>38</b> still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M₁ activation contributes to the cholinergic liabilities that were previously attributed to activation of the M₂ and M₃ receptors