Structural Optimization of the Diarylurea PSNCBAM-1, an Allosteric Modulator of Cannabinoid Receptor 1.

BACKGROUND: Structure-activity relationship studies improve the pharmacological and pharmacokinetic properties of a lead compound such as PSNCBAM-1, an allosteric modulator of the cannabinoid receptor 1. OBJECTIVES: Here, several derivatives of PSNCBAM-1 were synthesized with the aim of reducing the number of rings within its structure and enhancing the solubility of the compounds. The derivatives studied contain substituents previously shown to enhance binding of agonists (ie, a cyano group and a pyrimidine ring), with a reduced number of rings compared with the parent compound, PSNCBAM-1. METHODS: The synthesized compounds were tested for the enhancement of the binding of orthosteric cannabinoid receptor 1 agonist CP55,940 in the presence of varying concentrations of each test compound. Select compounds were also tested for their effects on cannabinoid receptor 1 inverse agonist SR141716A binding. The compounds were also subjected to computational analysis of drug-like properties and solubility. RESULTS: Consistent with a positive allosteric modulator for orthosteric ligand binding, compounds LDK1317 (12a), LDK1320 (12b), LDK1321 (6a), LDK1323 (8a), and LDK1324 (6b) all enhanced the binding of agonist CP55,940 to some degree. Reduction in the number of rings did not abolish the activity. The new lead compounds LDK1317 (12a) and LDK1321 (6a) showed improved drug-like properties and enhanced solubility in silico. CONCLUSIONS: In contrast to PSNCBAM-1, the synthesized compounds are analogs with fewer rings. The compounds LDK1317 (12a) and LDK1321 (6a) contained only 2 or 3 rings, respectively, and showed the binding parameters (KB = 110 nM, α = 2.3, and KB = 85 nM, α = 5.9). Further, the computationally predicted drug-like properties and solubility suggest these compounds are acceptable new lead compounds for further development of cannabinoid receptor 1 allosteric modulators. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor.

The cannabinoid type-1 (CB1) receptor, a G-protein-coupled receptor, is an attractive target for drug discovery due to its involvement in many physiological processes. Historically, drug discovery efforts targeting the CB1 receptor have focused on the development of orthosteric ligands that interact with the active site to which endogenous cannabinoids bind. Research performed over the last several decades has revealed substantial difficulties in translating CB1 orthosteric ligands into druggable candidates. The difficulty is mainly due to the adverse effects associated with orthosteric CB1 ligands. Recent discoveries of allosteric CB1 modulators provide tremendous opportunities to develop CB1 ligands with novel mechanisms of action; these ligands may potentially improve the pharmacological effects and enhance drug safety in treating the disorders by regulating the functions of the CB1 receptor. In this paper, we review and summarize the complex pharmacological profiles of each class of CB1 allosteric modulators, the development of new classes of CB1 allosteric modulators and the results from in vivo assessments of their therapeutic value.

Exploring 6-Azaindole and 7-Azaindole Rings for Developing Cannabinoid Receptor 1 Allosteric Modulators.

Introduction and Objective: Org27569 is a prototypical allosteric modulator of the cannabinoid receptor 1 (CB1). It belongs to the indole-2-carboxamide scaffold and has been intensively investigated in pharmacology and in structure-activity relationship (SAR) studies. Although azaindoles are rare in natural products and differ only by the presence of an extra ring nitrogen, they were demonstrated as valuable bioisosteres in many pharmacologically important molecules. To extend the SAR investigation of the indole-2-carboxamide class of CB1 allosteric modulators, azaindole (pyrrolopyridine) rings were used to replace the indole ring of Org27569 analogs to explore the potential of azaindole-2-carboxamides as CB1 allosteric modulators. Using 6- and 7-azaindole in lieu of the indole moiety within this class of CB1 allosteric modulators indeed improved the aqueous solubility. Materials and Methods: We synthesized 6- and 7-azaindole-2-carboxamides and their indole-2-carboxamide counterparts. The molecules were evaluated by [3H]CP55,940 binding and [35S]GTPγS binding assays for their allosteric modulation of the CB1 receptor. Results: The 7-azaindole-2-carboxamides lost the ability to bind to the CB1 receptor. The 6-azaindole-2-carboxamides (e.g., 3c and 3d) showed markedly reduced binding affinities to the CB1 receptor in comparison with their indole-2-carboxamide counterparts. However, they behaved similarly as indole-2-carboxamides in potentiating the orthosteric agonist binding and inhibiting the orthosteric agonist-induced G-protein coupling. The results indicated that some azaindole scaffolds (e.g., 6-azaindole) are worth further exploration, whereas the 7-azaindole ring is not a viable bioisostere of the indole ring in the Org27569 class of CB1 allosteric modulators.

Pyrimidinyl Biphenylureas: Identification of New Lead Compounds as Allosteric Modulators of the Cannabinoid Receptor CB1.

The allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB1) and antagonized G protein coupling. This compound demonstrated potent anorectic effects similar to the CB1 antagonist rimonabant that once was marketed for the treatment of obesity, suggesting a new chemical entity for the discovery of antiobesity drugs. To increase structural diversity of this class of CB1 ligands, we designed and synthesized two classes of novel analogues, in which the pyridine ring of 2 was replaced by a pyrimidine ring. These positively modulate the binding of the CB1 orthosteric agonist CP55,940 while exhibiting an antagonism of G-protein coupling activity. Interestingly, compounds 7d and 8d demonstrated ERK1/2 phosphorylation mediated via ß-arrestin unlike the orthosteric CP55,940 that does so in a G protein-dependent manner. These can serve as new lead compounds for the future development of CB1 allosteric modulators that show biased agonism and potentially antiobesity behavior via a new mechanism.