Table 5. Predicted Affinities and Cooperativities for VU0155094 across the Group III mGlus Using Calcium Assays with Chimeric G Proteins Reveals Distinct Receptor–PAM Interactions^a.

	mGlu4			mGlu7			mGlu8
	Glu	L-AP4	LSP4-2022	Glu	L-AP4	LSP4-2022	Glu	L-AP4	LSP4-2022
pKB	4.88 ± 0.03	4.88 ± 0.05d	4.97 ± 0.10	4.77 ± 0.18c	5.38 ± 0.22cd	5.10 ± 0.17e	5.07 ± 0.37	4.83 ± 0.07d	4.85 ± 0.08e
KB (μM)	13.3	13.2	10.6	17	4.2	8.0	8.6	14.7	14.0
log τB	n.a	n.a	n.a	–0.17 ± 0.03	–0.09 ± 0.04	–0.22 ± 0.06	–0.12 ± 0.03	–0.14 ± 0.04	–0.10 ± 0.06
τB	n.a	n.a	n.a	0.81	1.16	0.61	0.75	0.73	0.80
log β	0.16 ± 0.08fh	0.67 ± 0.27fi	0.33 ± 0.07j	0.68 ± 0.12gh	0.07 ± 0.03gi	–0.10 ± 0.10gj	0.08 ± 0.02h	0.05 ± 0.03i	0.05 ± 0.06j
β	1.4	4.7	2.1	4.8	1.2	0.8	1.2	1.1	1.1
log α	0.28 ± 0.07	–0.15 ± 0.30k	0.17 ± 0.13l	0.58 ± 0.13	0.39 ± 0.21	0.82 ± 0.26l	0.61 ± 0.39	0.92 ± 0.08k	0.93 ± 0.06l
α	1.9	0.71	1.5	3.8	2.4	6.6	4.1	8.3	8.6
n	6.2 ± 1.8	2.0 ± 0.2	2.2 ± 0.03	2.3 ± 0.4	6.7 ± 3.1	2.9 ± 1.2	4.6 ± 2.5	2.9 ± 0.4	3.0 ± 0.3
basal	6.9 ± 1.8	7.1 ± 0.7	7.6 ± 0.6	0.4 ± 2.3	3.3 ± 2.4	3.8 ± 0.8	3.3 ± 0.4	2.4 ± 0.3	2.3 ± 0.5
Emb	195.7	195.7	195.7	377.2	377.2	377.2	102.3	102.3	102.3

^aData were fitted from curves shown in Figure S4 (Supporting Information) using eq 2. The α value was shared between data sets, and the E_m was constrained to the maximal level of potentiation observed for that subtype between any combination of ligands in a given experiment. For statistical analyses, pK_B, log α, and log β values were compared between agonists at one receptor and then separately between receptors for a given agonist. All statistical tests were one-way ANOVA with a Tukey’s post-test to compare all columns. Data are comprised of three individual experiments performed in duplicate (mean ± SD values shown).

^bE_m value constrained to the maximal level of potentiation observed for that subtype between any combination of ligands in a given experiment; the mean is reported. All p values <0.05.

^cpK_B between mGlu₇/glutamate versus mGlu₇/L-AP4.

^dpK_B between mGlu_7/L-AP4 versus mGlu₄/L-AP4 and mGlu₈/L-AP4.

^epK_B between mGlu_7/LSP4-2022 versus mGlu₈/LSP4-022.

^fLog β between mGlu_4/glutamate versus mGlu₄/L-AP4.

^gLog β between mGlu_7/glutamate versus mGlu₇/L-AP4 and mGlu₇/LSP4-2022.

^hLog β between mGlu_7/glutamate versus mGlu₄/glutamate and mGlu₈/glutamate.

ⁱLog β between mGlu₄/L-AP4 versus mGlu₇/L-AP4 and mGlu₈/L-AP4.

^jLog β between mGlu₄/LSP4-2022 versus mGlu₇/LSP4-2022 and mGlu₈/LSP4-2022.

^kLog α of mGlu₄/L-AP4 versus mGlu₈/L-AP4.

^lLog α of mGlu₄/LSP4-2022 versus mGlu₇/LSP4-2022 and mGlu₈/LSP4-2022.