Estimates of allosteric modulator affinities from modulator concentration-response curves in the presence of an EC20 (PAMs) or EC80 (NAMs) concentration of agonist
Operational analysis of potency curves was performed by simultaneously applying eqs. 6 and 7, with pKA constrained to 6.155, to derive pKB and logβ estimates for modulators. Data represent the mean ± S.E.M. from at least three independent determinations.
| Modulator | PAM pEC50/NAM pIC50 | Operational Analysis of Potency Curves | Logβ′ (Fold Shift) | |
|---|---|---|---|---|
| pKB | logβ | |||
| CDPPB | 7.16 ± 0.08 | 6.85 ± 0.08 | 0.56 ± 0.05 | 0.78 ± 0.14 (7.1) |
| VU29 | 7.25 ± 0.14 | 6.65 ± 0.20 | 0.88 ± 0.13 | 0.85 ± 0.12 (8.8) |
| CPPHA | 6.35 ± 0.19 | 5.51 ± 0.09 | 0.76a | 0.76 ± 0.13 (7.8) |
| VU0357121 | 6.72 ± 0.12 | 6.46 ± 0.10 | 0.48 ± 0.05 | 0.32 ± 0.03 (2.1) |
| VU0364289 | 6.50 ± 0.11 | 5.50 ± 0.19 | 0.86a | 0.86 ± 0.06 (7.6) |
| VU0092273b | 7.05 ± 0.08b | 6.77 ± 0.10 | 0.51 ± 0.05 | 0.51 ± 0.05 (3.3) |
| VU0360172b | 7.45 ± 0.07b | 7.13 ± 0.05 | 0.53 ± 0.04 | 0.44 ± 0.06 (2.8) |
| VU0405398 | 7.79 ± 0.12 | 7.52 ± 0.09 | 0.34 ± 0.05 | 0.29 ± 0.03 (2.0) |
| VU0415051 | 7.91 ± 0.09 | 7.82 ± 0.05 | 0.41 ± 0.04 | 0.34 ± 0.04 (2.3) |
| VU0405386 | 8.65 ± 0.13 | 8.30 ± 0.13 | 0.50 ± 0.05 | 0.70 ± 0.07 (5.3) |
| MPEP | 8.07 ± 0.07 | 8.10 ± 0.17 | −100c | N.A. |
| M-5MPEP | 6.66 ± 0.09 | 6.85 ± 0.13 | −0.41 ± 0.03 | N.A. |
| VU0285683 | 6.93 ± 0.15 | 7.06 ± 0.15 | −100c | N.A. |
| VU0366248 | 5.85 ± 0.13 | 6.24 ± 0.13 | −0.70 ± 0.13 | N.A. |
| VU0366249 | 5.74 ± 0.20 | 5.73 ± 0.19 | −0.22 ± 0.01 | N.A. |
| VU0366058 | 6.52 ± 0.27 | 6.64 ± 0.11 | −100c | N.A. |
pEC50, negative logarithm of the concentration of modulator that caused half-maximal potentiation of a low concentration (EC20) of glutamate (eq. 5); pIC50, negative logarithm of the concentration of modulator that caused half-maximal inhibition of a submaximal concentration (EC80) of glutamate (eq. 5); pKB, negative logarithm of the equilibrium dissociation constant of an allosteric modulator; logβ, logarithm of the efficacy cooperativity factor β; logβ′, logarithm of the efficacy cooperativity factor β estimated from the maximal leftward shift of the glutamate curve caused by an allosteric modulator; N.A., not applicable.
↵a For PAMs that potentiated up to the maximal response of glutamate, logβ was constrained to this value for estimations of affinities.
↵b Potentiator concentration-response curves were reported previously by Noetzel et al. (2012).
↵c For NAMs that abolished the response to glutamate, β = 0 was assumed and therefore logβ was constrained to −100.