Variously substituted 2-oxopyridine derivatives: Extending the structure-activity relationships for allosteric modulation of the cannabinoid CB2 receptor

Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: from Orthosteric and Allosteric Modulators to Dualsteric/Bitopic Ligands

“…Although ligand bias was not estimated for FM-6b , this parent agonist was both more potent and more efficacious in the cAMP inhibition assay than the βarrestin2 recruitment, indicating that the parent agonist may display functional selectivity for Gα i/o -dependent signaling. EC-21a has not previously been shown to display a ligand bias, and in the present study its absence of activity alone makes estimates of ligand bias for the compound impracticable. Among the new derivatives, only FD-32a showed greater activity in the βarrestin2 assay relative to the cAMP inhibition assay.…”

“…However, this strategy is hampered by the lack of knowledge regarding allosteric site(s), location, and structure. , Allosteric modulators devoid of intrinsic activity alter receptor signaling through conformational changes in the receptor, modifying the affinity and/or efficacy of an orthosteric ligand without showing intrinsic effects per se . One unique feature of allosteric ligands is agonist dependence, better known as probe dependence, ultimately implying that the same allosteric ligand may differentially modulate the activity of different orthosteric ligands. , Moreover, allosteric ligands may alter the specific signal bias of orthosteric ligands or display ligand bias themselves. − Allosteric ligands can be classified as positive (PAM), negative (NAM), or neutral (NAL) allosteric modulators depending on the type of modulation on the affinity and/or efficacy of the orthosteric ligand. Allosteric ligands have been found to present a generally reduced side effect profile compared to orthosteric ligands but often suffer from reduced efficacy. , To overcome this problem, a new approach in medicinal chemistry is to encode both orthosteric and allosteric properties within a single therapeutic agent, a bitopic/dualsteric ligand, that bridges two topographically distinct ligand-binding domains.…”

Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB2R)

“…The nitrogen atom in position 1 and the 4-methyl cyclohexyl group in position 3 of LV62 moiety were selected to connect in position N (1) of the central core of EC21a , obtaining respectively the A ( JR22a, JR26a, JR58a, JR60a, JR61a, JR64a compounds) and B ( JR14a, JR16a compounds) series. Previous structural activity relation (SAR) studies on 1,8-naphthyridin-2(1 H )-one-3-carboxamide derivatives ( Lucchesi et al, 2014 ; Cooper et al, 2018 ) and on EC21a analogues ( Gado et al, 2019 ; Gado et al, 2021 ) indicated these positions as the most suitable to chemical modifications without significantly compromising activity. The choice of the correct linker plays a crucial role in allowing the two pharmacophores to interact correctly with the respective binding site.…”

Rational drug design of CB2 receptor ligands: from 2012 to 2021

“…To further study the SAR of 101, structural modication was conducted respectively by uorine atom or by chlorine atom in ortho position of the benzylic group at N-1 position and by a cycloheptane-carboxamide at C-3 position of the central core, showed positive allosteric behavior on CB2. 87 Compound 103 was found by ligand-based virtual screen, which was a moderate activity CB2 agonist with high selectivity. To obtain the greater CB2 potency with appropriate physicochemical and ADME properties for future evaluation in vivo, Russell' team replaced the alkyl chain with aryl chain.…”

“…To further study the SAR of 101, structural modification was conducted respectively by fluorine atom or by chlorine atom in ortho position of the benzylic group at N-1 position and by a cycloheptane-carboxamide at C-3 position of the central core, showed positive allosteric behavior on CB2. 87 …”