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. Author manuscript; available in PMC: 2016 Mar 18.
Published in final edited form as: Neuron. 2015 Feb 26;85(6):1305–1318. doi: 10.1016/j.neuron.2015.02.008

Table 1.

Optimization of pH dependence of GluN1/GluN2B antagonists as a function of N-alkyl chain length and steric bulk.

graphic file with name nihms-662954-f0006.jpg
Ra # Chain amine pKab Fold increase in ionized speciesc N-substituent Volume Angstroms3 IC50 pH 6.9 H.M (N) d IC50 pH 7.6 HM (N) d IC50(7.6) /IC50(6.9) Ratio e
-H (S) 93-4 8.6 1.1 -- 0.036 (10) 0.045 (11) 1.3
-CH3 (S) 93-2 8.0 1.3 19.8 0.050 (29) 0.13 (22) 2.6
-CH2CH3 (S) 93-5 8.1 1.2 33.4 0.021 (22) 0.067 (14) 3.2
-CH2CH2CH3 (S) 93-6 8.1 1.2 47.9 0.094 (17) 0.48 (16) 5.1
-CH2CH2CH2CH3 (S) 93-31 8.1 1.2 62.3 0.19 (32) 1.8 (23) 9.4
-CH2CH2CH2CH2CH3 (S) 93-87 8.1 1.2 77.5 0.16 (9) 0.60 (6) 3.8
-CH(CH3)2 (S) 93-115 8.2 1.2 47.9 0.19 (11) 0.62 (12) 3.3
-CH2CH(CH3)2 (S) 93-97 8.0 1.3 63.6 1.1 (21) 3.2 (31) 2.9
a

Compound synthesis described in Tahirovic et al., (2008); all compounds were the S enantiomer.

b

The pKa of the chain nitrogen was calculated using ACD/pKa DB 12.00, www.acdlabs.com.

c

Fold increase ionized species when reducing pH from 7.6 (pH1) to 6.9 (pH2) was calculated using equation (3): the Henderson-Hasselbach equation as (1 + 10(pH2 - pKa)) / (1 + 10(pH1 - pKa))

d

IC50 values for inhibition of GluN1/GluN2B expressed in Xenopus oocytes were determined as described in the Methods from composite inhibition curves. N is the number of oocytes recorded; measurements made for oocytes at both pH values in the same experiment. The slope varied between −0.70 to −1.09; maximum inhibition 79-100%.

e

The pH-dependent potency ratio for inhibition of GluN1/GluN2B receptors.

See also Figure S1 and Table S6.