2022
DOI: 10.3389/fchem.2022.984069
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Design, synthesis and biological evaluation of novel orthosteric-allosteric ligands of the cannabinoid receptor type 2 (CB2R)

Abstract: It is well known that G protein–coupled receptors (GPCRs) assume multiple active states. Orthosteric ligands and/or allosteric modulators can preferentially stabilize specific conformations, giving rise to pathway-biased signaling. One of the most promising strategies to expand the repertoire of signaling-selective GPCR activators consists of dualsteric agents, which are hybrid compounds consisting of orthosteric and allosteric pharmacophoric units. This approach proved to be very promising showing several adv… Show more

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Cited by 11 publications
(21 citation statements)
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“…Both cases are agonists targeting cannabinoid receptor 2 (CB 2 R), either made by the combination of orthosteric and allosteric (but with unclear binding site) scaffolds 65 or two orthosteric scaffolds. 66 After docking experiments, both agonists were suggested to bind the orthosteric site and an allosteric site outside the 7TM bundle, which is site VIII for the hetero-bivalent ligand 65 and an unreported site between TM1 and TM7 for the homo-bivalent ligand. 66 Their linkers were predicted to insert into the interspace between TM a-helixes, although such a binding pose may endure certain steric effects.…”
Section: Gpcrmentioning
confidence: 99%
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“…Both cases are agonists targeting cannabinoid receptor 2 (CB 2 R), either made by the combination of orthosteric and allosteric (but with unclear binding site) scaffolds 65 or two orthosteric scaffolds. 66 After docking experiments, both agonists were suggested to bind the orthosteric site and an allosteric site outside the 7TM bundle, which is site VIII for the hetero-bivalent ligand 65 and an unreported site between TM1 and TM7 for the homo-bivalent ligand. 66 Their linkers were predicted to insert into the interspace between TM a-helixes, although such a binding pose may endure certain steric effects.…”
Section: Gpcrmentioning
confidence: 99%
“…66 After docking experiments, both agonists were suggested to bind the orthosteric site and an allosteric site outside the 7TM bundle, which is site VIII for the hetero-bivalent ligand 65 and an unreported site between TM1 and TM7 for the homo-bivalent ligand. 66 Their linkers were predicted to insert into the interspace between TM a-helixes, although such a binding pose may endure certain steric effects. 65 Since, to date, there were neither attempts to directly link the orthosteric ligand and an allosteric ligand ensured to bind GPCR outside the 7TM bundle nor crystal structures of this type, it is still unclear whether such a dualsteric strategy is attainable.…”
Section: Gpcrmentioning
confidence: 99%
See 1 more Smart Citation
“…A separate group consists of compounds that are able to simultaneously interact with both orthosteric and allosteric sites, which are classified as bitopic GPCR ligands [74,[76][77][78][79][80][81]. They have two pharmacophores, one of which binds with high affinity to the orthosteric site, while the other, with lower affinity, binds to the allosteric site.…”
Section: Classification Of Allosteric Gpcr Regulatorsmentioning
confidence: 99%
“…This approach is especially promising for pathologies where the endogenous ligand is absent, like for acetylcholine deficiency in neurodegenerative diseases like AD . Two different approaches toward dualsteric heterobivalent ligands for CB 2 R have very recently been described by Gado et al and us. Gado et al discovered the first CB 2 R-selective PAM ( 1 , Figure ) and recently also obtained the first dualsteric ligand by linking their PAM to a structurally related orthosteric ligand. , Their dualsteric lead compound had anti-inflammatory effects in a human microglial cell inflammatory model and antinociceptive activity in vivo , observed in an experimental mouse model of neuropathic pain . In a recent work, we synthesized the dualsteric CB 2 R ligand B3 ( cf.…”
Section: Introductionmentioning
confidence: 99%