Evaluation of (Z)-2-((1-benzyl-1H-indol-3-yl)methylene)-quinuclidin-3-one analogues as novel, high affinity ligands for CB1 and CB2 cannabinoid receptors

Abstract

A small library of N-benzyl indolequinuclidinone (IQD) analogs has been identified as a novel class of cannabinoid ligands. The affinity and selectivity of these IQDs for the two established cannabinoid receptor subtypes, CB1 and CB2, was evaluated. Compounds 8 (R=R2=H, R1=F) and 13 (R=COOCH3, R1=R2=H) exhibited high affinity for CB2 receptors with Ki values of 1.3nM and 2.5 nM, respectively, and had lower affinities for the CB1 receptor (Ki values of 9.1nM and 85.7 nM, respectively). Compound 13 had the highest selectivity of all the compounds examined, and represents a potent cannabinoid ligand with 35-times greater selectivity for CB2R over CB1R.

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

“…1C; PNR-4-20 and Fig. 1D; PNR-4-02) classes (29, 41). Initial competition binding studies, employing the high affinity CB 1 /CB 2 R agonist [ 3 H]CP-55,940 (42), were conducted to determine the affinity of the cannabinoid ligands examined (Fig.…”

“…Although a number of structurally diverse classes of cannabinoid ligands have been developed (25–27), CB 1 R agonists characterized to date exhibit relatively equivalent coupling to both G-protein and β-arrestin 2 pathways (28). Our group recently characterized a novel class of indole quinulidinone (IQD) analogues that exhibit high nanomolar affinity for CB 1 Rs (29), and act as partial to full CB 1 R agonists for modulation of the Gi/Go-coupled intracellular effector adenylyl cyclase (30). Although IQD analogues have been shown to clearly couple CB 1 Rs to G protein-dependent pathways, the ability of compounds in this class to produce CB 1 R-mediated G protein-independent recruitment of β-arrestin 2 has yet to be determined.…”

Synthesis and structure investigation of novel pyrimidine-2,4,6-trione derivatives of highly potential biological activity as anti-diabetic agent

“…For example, pyrimidine-2,4,6-trione derivatives are known to have as anti-hypertensive [2], anti-cancer [3], anti-convulsant [4] antiinflammatory [5], and anti-psychotic properties [6]. Because of the biological activities of these compounds, pyrimidine-2,4,6-triones (PYT) are widely used as a synthons in the design of antitumor agents.…”

Synthesis, characterization and cytotoxic investigations of novel bis(indole) analogues besides antimicrobial study

“…In particular, C-3-substituted indoles are important building blocks for the synthesis of many biologically active compounds which possess antimalarial (Agarwal et al, 2005), inhibitors of HIV-1 (Meanwell et al, 2009), antimicrobial (Lakshmi et al, 2010;Reddy et al, 2011), antioxidant (Lakshmi et al, 2010), anticancer (Lakshmi et al, 2010), cytotoxic (Gu et al, 1999), inhibitors of hepatitis C virus (Jin et al, 2014), anti-diabetic (Rajesh et al, 2007), and neuro protective (Mohareb et al, 2011) activities. On the other hand, N-1 and C-3-substituted indole derivatives have been found to play an important role in many biologically active compounds especially with antiinflammatory (Hall et al, 2008;Singh et al, 2008), anticancer (Singh et al, 2008;Madadi et al, 2014), anti-nociceptive (Adam et al, 2010) and antipsychotic (Madadi et al, 2013) activities. Marine indole alkaloids have emerged as an important structural class exhibiting antiviral, antimicrobial and antitumor activity (Dembitsky et al, 2005;Bao et al, 2005;Oh et al, 2005Oh et al, , 2006.…”