TY - JOUR

T1 - Improved synthetic route for the GluN2-specific NMDA receptor glycine site agonist AICP

AU - Zhao, Fabao

AU - Rouzbeh, Nirvan

AU - Hansen, Kasper B.

AU - Clausen, Rasmus P.

PY - 2020/3/31

Y1 - 2020/3/31

N2 - (R)-2-Amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid (AICP) is a N-methyl-D-aspartate (NMDA) receptor glycine site agonist with unprecedented high potency in the low nanomolar range, and a GluN2 subunit-dependent pharmacological profile in terms of potency and agonist efficacy (Jessen et al., 2017 [1]). Here, we report a scalable, practical and cost-efficient synthetic route for AICP, which is an improvement compared to the previously reported route. This improved synthetic route includes a versatile diphenylmethylester (DPM) protection for the amino acid moiety, which can be widely used in the synthesis of other amino acid ligands. Further functional evaluation of AICP at the different ionotropic glutamate receptor (iGluR) classes demonstrates that high affinity binding of AICP to the orthosteric binding site is selective for NMDA receptors over AMPA and kainate receptors. Furthermore, high affinity binding of AICP is not observed at GluN3A, GluN3B, and GluD2 subunits, which also bind glycine and D-serine. Thus, the new approach described here enables scalable synthesis of AICP for the use as a pharmacological tool compound to study the involvement of neuronal NMDA receptor subtypes in normal brain function and disease.

AB - (R)-2-Amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid (AICP) is a N-methyl-D-aspartate (NMDA) receptor glycine site agonist with unprecedented high potency in the low nanomolar range, and a GluN2 subunit-dependent pharmacological profile in terms of potency and agonist efficacy (Jessen et al., 2017 [1]). Here, we report a scalable, practical and cost-efficient synthetic route for AICP, which is an improvement compared to the previously reported route. This improved synthetic route includes a versatile diphenylmethylester (DPM) protection for the amino acid moiety, which can be widely used in the synthesis of other amino acid ligands. Further functional evaluation of AICP at the different ionotropic glutamate receptor (iGluR) classes demonstrates that high affinity binding of AICP to the orthosteric binding site is selective for NMDA receptors over AMPA and kainate receptors. Furthermore, high affinity binding of AICP is not observed at GluN3A, GluN3B, and GluD2 subunits, which also bind glycine and D-serine. Thus, the new approach described here enables scalable synthesis of AICP for the use as a pharmacological tool compound to study the involvement of neuronal NMDA receptor subtypes in normal brain function and disease.

KW - Amino acid protection

KW - Ethyl 4-bromo-1H-indole-2-carboxylate

KW - Subunit selectivity

KW - Two-electrode voltage-clamp electrophysiology

U2 - 10.1016/j.tetlet.2020.151653

DO - 10.1016/j.tetlet.2020.151653

M3 - Letter

AN - SCOPUS:85078544699

VL - 61

JO - Tetrahedron Letters

JF - Tetrahedron Letters

SN - 0040-4039

IS - 12

M1 - 151653

ER -