TABLE 3

AZ12559322 is a potent and selective mGlu2 PAM

TargetPAM EC50 (Maximum Effect)Agonist EC50
μMμM
HmGlu2 (%)a0.01 (77.5)>25
HmGlu1b>25N/A
HmGlu3b>25>25
HmGlu4b>25>25
HmGlu5 (%)b0.7692 (66.8)>25
HmGlu6b>25>25
HmGlu7b>25>25
HmGlu8b>25>25
Operational model parameters
 Log αβ (αβ)c0.99 ± 0.12 (9.77)
 Log KB (KB, nM)c−7.17 ± 0.12 (68)
 n1.4 ± 0.2
 Basal2.9 ± 2.0
 Maximum100.9 ± 0.8
 Log EC50 (nM)d−7.78 ± 0.01 (17)
  • hCaR, human calcium receptor; HmGlu, human metabotropic glutamate receptor; N/A, not available.

  • a Data from 5′-O-(3-[35S]thio)triphosphate binding in Chinese hamster ovary cell line expressing human mGlu2.

  • b mGlu receptor selectivity data from fluorescence-based binding assays wherein HEK293 cell lines express chimeric hmGlu receptor/hCaR.

  • c Data for cooperativity (αβ) and allosteric modulator affinity (KB) obtained from fitting functional data from the GIRK assay in WT mGlu2 (Fig. 5B) to the operational model of allosterism as outlined in the Materials and Methods.

  • d Functional potencies (EC50) were obtained from interpolating data from the GIRK assay curve fit in Fig. 5B at the EC20 glutamate concentration and plotting a concentration-response curve as outlined in the Materials and Methods.