Structure–activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators

Abstract

A series of substituted 1H-indole-2-carboxamides structurally related to compounds Org27569 (1), Org29647 (2) and Org27759 (3) were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure-activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound (45) had an IC50 value of 79 nM which is ~ 2.5 and 10 fold more potent than the parent compounds 3 and 1, respectively. These compounds appeared to be negative allosteric modulators at the CB1 receptor and dose-dependently reduced the Emax of agonist CP55,940. These analogs may provide the basis for further optimization and use of CB1 allosteric modulators.

Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution

“…22, 24 In these assays, CHO cells that overexpress the promiscuous Gα 16 protein (RD-HGA16 cells, Molecular Devices) were engineered to stably express the human CB1 or CB2 receptor. Compounds were evaluated for their ability to inhibit the mobilization of intracellular calcium levels stimulated by CP55,940.…”

Synthesis and biological evaluation of indole-2-carboxamides bearing photoactivatable functionalities as novel allosteric modulators for the cannabinoid CB1 receptor

“…These conformation-restricted moieties might cause steric interference when the ligands bearing these photophores interact with the CB1 allosteric site. In earlier SAR studies, it was also found that cyclic substituents on the 4-position of the phenyl ring of this scaffold was not as tolerated as acyclic substituents [32–34]. The results of 28 and 29 showed that azido and TFMD moieties located at the 4-position of the phenyl ring indeed reduced the binding capacity of the ligands to the allosteric site of CB1 receptor.…”

Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities

“…An n-propyl chain substitution enhances the allosteric modulation of orthosteric ligand binding, whereas an n-hexyl chain enhances the affinity of the allosteric modulator for CB 1 (Khurana et al, 2014). Substitution with short chain alkyl groups such as methyl improves allostery at CB 1 in calcium mobilization assays (Nguyen et al, 2015). …”

“…A fluoro substitution at the C5 position demonstrates improved allostery over a chloro substitution (Nguyen et al, 2015). …”

“…For example, ORG27569 demonstrated positive allosteric modulation for agonist CP55,940 binding and was internalized as expected for an activated receptor (Price et al, 2005; Ahn et al, 2012) and thus may be classified as a PAM. However, this is an inhibitor of G-protein coupling (Price et al, 2005; Mahmoud et al, 2013) and demonstrates negative modulation of CP55,940 induced calcium mobilization (Nguyen et al, 2015) and thus is also reported as a NAM. Similarly, PSNCBAM-1 demonstrated PAM activity for CP55,940 binding (Horswill et al, 2007) and CP55,940 induced ERK1/2 phosphorylation (Khurana et al, 2017).…”