Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 3. Synthesis, Structure−Affinity Relationships, and Pharmacological Characterization of 6-Substituted 4-Quinolone-3-carboxamides as Highly Selective Cannabinoid-2 Receptor Ligands

Abstract

A set of quinolone-3-carboxamides 2 bearing diverse substituents at position 1, 3, and 6 of the bicyclic nucleus was prepared. Except for six compounds exhibiting Ki>100 nM, all the quinolone-3-carboxamides 2 proved to be high affinity CB2 ligands, with Ki values ranging from 73.2 to 0.7 nM and selectivity [SI=Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only 2ah exhibiting a reverse selectivity (SI<1). In the formalin test of peripheral acute and inflammatory pain in mice, 2ae showed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, 2e was inactive per se and antagonized the effect of a selective CB2 agonist. Finally, 2g and 2p exhibited CB2 inverse agonist-like behavior in this in vivo test. However, two different functional assays carried out in vitro on 2e and 2g indicated for both compounds an overall inverse agonist activity at CB2 receptors.

Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs

“…For example, cannabinoid type-2 receptor agonists have been shown to produce anti-angiogenic and anti-proliferative effects in the treatment of various forms of cancers (Vidinsky et al, 2012), to reduce chronic neuropathic pain (Wilkerson et al, 2012), and to beneficially modulate cytokine levels in immunologically-based disease states (Cabral and Griffin-Thomas, 2009). Since cannabinoid type-2 receptors participate in inflammatory processes via modulation of cytokine release, both agonists (Ehrhart et al, 2005) and newly developed classes of antagonists/inverse agonists (Lunn et al, 2008; Pasquini et al, 2011; Pasquini et al, 2010; Pasquini et al, 2012) have been shown to reduce inflammation and hyperalgesia associated with several disease states. Importantly, four indole quinuclidine compounds examined in this study demonstrate from 5-, to over 30-, fold selectivity for binding to cannabinoid type-2 relative to type-1 receptors (Table 3) (Madadi et al, 2013).…”

A convenient approach to the synthesis of substituted 2-(methylamino)quinoline-3-carboxamides

“…Крім цього, ці спо-луки є потенційними інгібіторами β-секретази (BACE) [13], ацетилхолінестерази [14], тирозин-кінази [15], а також агоністами каннабіноїдних рецепторів СВ1 та СВ2 [16][17][18][19].…”

Latest Advances in Novel Cannabinoid Cb 2 Ligands for Drug Abuse and Their Therapeutic Potential

“…Except for six compounds exhibiting K i >100 nM, all the quinolone-3-carboxamides proved to be high-affinity CB 2 ligands, with K i values ranging from 73.2 to 0.7 nM and selectivity (CB 1 /CB 2 ) varying from >14,285 to 1.9. Compound 29 (Figure 5) in particular has very high CB 2 receptor affinity (K i = 0.7 nM) and good selectivity of 14,285-fold for this receptor [70]. Recently, in their continuing effort to explore SAR for quinolones binding at CB receptors, they discovered the 8-methoxy derivative 30 (Figure 5) endowed with the higher affinity and selectivity (CB 2 : K i = 0.6 nM; CB 1 : K i >10,000 nM; selectivity >16,666), which behaved as an inverse agonist [71].…”