TABLE 3

Affinity estimates (pKB) for allosteric modulators at mGlu5-wt and mutants derived from operational model analysis of interactions with glutamate

Data represent the mean ± S.E.M. from 4–8 independent experiments performed in duplicate.

MutationMPEPVU0360172 (Nicotinamide)VU0403602 (Picolinamide)VU0360173 (Nicotinamide)VU0405398 (Picolinamide)VU0415051 (Nicotinamide)VU0405386 (Picolinamide)
R5-wt (poly)8.58 ± 0.17#6.68 ± 0.158.13 ± 0.265.45 ± 0.276.94 ± 0.177.34 ± 0.188.04 ± 0.26
R647A8.89 ± 0.196.29 ± 0.127.99 ± 0.094.91 ± 0.146.94 ± 0.107.28 ± 0.257.74 ± 0.12
I650A8.62 ± 0.037.12 ± 0.197.97 ± 0.13N.D.7.29 ± 0.15N.D.8.10 ± 0.15
G651F7.53 ± 0.18*5.86 ± 0.18*6.50 ± 0.18*No PAM5.99 ± 0.28*6.94 ± 0.197.14 ± 0.08
P654S7.10 ± 0.06*6.39 ± 0.247.33 ± 0.16<55.80 ± 0.27*5.69 ± 0.46*7.81 ± 0.27
P654F4.11 ± 0.21*5.91 ± 0.175.99 ± 0.26*No PAM5.33 ± 0.27*5.25 ± 0.19*6.23 ± 0.22*
S657C8.32 ± 0.08N.D.7.41 ± 0.17N.D.6.99 ± 0.316.78 ± 0.127.68 ± 0.06
Y658V6.57 ± 0.13*#No PAMNo PAMNo PAM4.97 ± 0.35*No PAMNo PAM
P742S8.07 ± 0.17*6.57 ± 0.107.50 ± 0.124.65 ± 0.176.83 ± 0.207.09 ± 0.047.96 ± 0.16
L743V8.04 ± 0.10*#6.97 ± 0.157.93 ± 0.145.46 ± 0.126.77 ± 0.117.75 ± 0.208.36 ± 0.10
N746A8.30 ± 0.066.66 ± 0.107.99 ± 0.11N.D.6.50 ± 0.23N.D.8.06 ± 0.17
T780A7.36 ± 0.02*No PAM6.03 ± 0.13*No PAM5.59 ± 0.05*5.82 ± 0.40*5.32 ± 0.24*
W784A5.50 ± 0.29*6.76 ± 0.147.09 ± 0.34*5.03 ± 0.446.23 ± 0.207.14 ± 0.157.53 ± 0.14
V788A7.89 ± 0.13*7.28 ± 0.178.43 ± 0.206.28 ± 0.187.84 ± 0.148.07 ± 0.198.79 ± 0.08
F792A8.93 ± 0.047.25 ± 0.338.03 ± 0.024.80 ± 0.207.34 ± 0.208.06 ± 0.247.02 ± 0.47*
S806A8.36 ± 0.06N.D.N.D.N.D.N.D.N.D.7.29 ± 0.45
S808A6.98 ± 0.18*6.15 ± 0.306.47 ± 0.10*No PAM6.28 ± 0.097.20 ± 0.447.48 ± 0.20
S808T6.90 ± 0.06*6.59 ± 0.207.15 ± 0.33*5.04 ± 0.336.40 ± 0.236.36 ± 0.26*8.05 ± 0.27
A809V6.52 ± 0.12*#5.64 ± 0.19*6.52 ± 0.21*No PAMNo PAM5.56 ± 0.12*6.22 ± 0.14*
A809G7.18 ± 0.04*5.93 ± 0.186.59 ± 0.05*5.13 ± 0.135.88 ± 0.05*6.28 ± 0.11*6.60 ± 0.24*
C815A8.35 ± 0.056.58 ± 0.227.29 ± 0.26*4.81 ± 0.136.73 ± 0.357.26 ± 0.117.63 ± 0.15
  • N.D., not determined; No PAM, no observed positive allosteric modulation.

  • * P < 0.05 vs. wild-type value, one-way analysis of variance (ANOVA), Dunnett’s post-test; #data previously reported (Gregory et al., 2012).