biostudies-literatureGregory KJNIDA NIH HHSNIMH NIH HHSNINDS NIH HHS860-75https://www.ebi.ac.uk/biostudies/studies/S-EPMC3477233biostudies-literatureUnknown82(5)Drug discovery programs increasingly are focusing on allosteric modulators as a means to modify the activity of G protein-coupled receptor (GPCR) targets. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, which allows for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator that can alter receptor pharmacological characteristics. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of orthosteric agonists. Established approaches for estimation of affinity and efficacy values for orthosteric ligands are not appropriate for allosteric modulators, and this presents challenges for fully understanding the actions of novel modulatMolecular pharmacologyInvestigating metabotropic glutamate receptor 5 allosteric modulator cooperativity, affinity, and agonism: enriching structure-function studies and structure-activity relationships.PMC3477233F32 MH088234R01 NS031373U54 MH0846591R01-DA023947U19 MH0970565U54-MH84659-03S1R01 MH062646F32-NS071746F32-MH088234-022R01-NS031373-16A25U54-MH84659-032R01-MH062646-13R01 DA023947F32 NS071746Conn PJNiswender CMNoetzel MJZhou YFelts ASGregory KJStauffer SRRodriguez ALLindsley CWVinson PNEmmitte KAChun ACRook JMChauder BAfalseInvestigating metabotropic glutamate receptor 5 allosteric modulator cooperativity, affinity, and agonism: enriching structure-function studies and structure-activity relationships.Drug discovery programs increasingly are focusing on allosteric modulators as a means to modify the activity of G protein-coupled receptor (GPCR) targets. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, which allows for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator that can alter receptor pharmacological characteristics. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of orthosteric agonists. Established approaches for estimation of affinity and efficacy values for orthosteric ligands are not appropriate for allosteric modulators, and this presents challenges for fully understanding the actions of novel modulat2012-01-01T00:00:00Z2012 Nov2025-04-18T14:07:25.512Z2019-03-27T00:59:18ZS-EPMC34772332286369310.1124/mol.112.080531