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• W2414984505 abstract "The past decade has witnessed a dramatic increase inthe identification of allosteric modulators of G-protein-coupledreceptor(GPCR)activity.Concomitantly,severalnew perspectives and hypotheses regarding the wayligands regulate GPCR signalling have also emerged.Here, we briefly discuss how the concepts of collateralefficacy and permissive agonism–antagonism intersectthe field of allosteric GPCR modulation. Despite thechallenges associated with detecting and quantifyingthemyriadofpossibleallostericeffectsonGPCRactivity,it is proposed that allosteric ligands offer the excitingprospect of engendering stimulus-bias in orthostericligand signalling, thus paving the way for not only re-ceptor-selective but also signalling-pathway-selectivetherapies.IntroductionThe seven-transmembrane-spanning G-protein-coupledreceptors (GPCRs) account for >1% of the human genomeand represent the targets for nearly 30% of all medicinescurrently on the market [1,2]. To date, the majority ofidentified drugs that target GPCRs interact with the re-ceptor orthosteric site (i.e. the same domain recognized bythe endogenous agonist for the receptor) [3] (see Glossary).Thus,theonlypossiblemodeofinteractionbetweenorthos-tericligandsactingatacommonreceptorsiteisoneofsterichindrance due to mutually exclusive binding. If receptorblockade is the desired functional endpoint, the adminis-tered orthosteric ligand should be a competitive antagonistorinverseagonist.Ifreceptorstimulationisthetherapeuticgoal,theorthostericdrugshouldbeanagonist,butonethatwill act in place ofthe endogenous agonist.Inall cases, it isassumed thatthequalityofthe signal generated bya givenagonist is not influenced by the presence of another orthos-teric ligand, although the magnitude of the signal mightchange. However, the past decade has witnessed a surge inthe number of ligands that target GPCRs by binding toallosteric sites on the receptors (i.e. binding domains thatare topographically distinct from the orthosteric site) [4].The binding of an allosteric ligand to its site causes aconformational change in the receptor protein that istransmitted to the orthosteric site (and vice versa), inessence creating a ‘new’ GPCR with its own set of bindingand functional properties. Unless this allosteric change ischaracterized by extremely high negative cooperativity,such that the orthosteric ligand can never bind to the newGPCR conformation induced by the modulator, the charac-teristic feature of the allosteric interaction is that the re-ceptor will co-bind both an orthosteric and an allostericligand. Thus, allosteric ligands can introduce texture intopharmacological responses by modifying the affinity or thesignal imparted to the receptor by the concomitant bindingof the orthosteric ligand. This article focuses on the con-sequences of texture in GPCR responses and the implica-tionsofsomeofthenewer conceptsinpharmacologyfor thestudy of GPCR allosterism.Allosteric GPCR ligands: modulators and agonistsAllosteric ligands are also called allosteric modulatorsbecause they can alter the binding affinity or the signalimparted to the cell by an orthosteric ligand. The simplestallosteric effect occurs when only the affinity of an orthos-teric ligand for its receptor changes. An allosteric ternarycomplexmodel(ATCM)(Box1)hasbeensuccessfullyusedtoquantifythisbehaviourintermsoftheaffinityofeachligandOpinion" @default.
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• W2414984505 date "2007-01-01" @default.
• W2414984505 modified "2023-09-27" @default.
• W2414984505 title "Allosteric GPCR modulators: taking advantage of permissive receptor" @default.
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