Improved synthetic route for the GluN2-specific NMDA receptor glycine site agonist AICP. Issue 12 (19th March 2020)

• Record Type: Journal Article
• Authors: Zhao, Fabao; Rouzbeh, Nirvan; Hansen, Kasper B.; Clausen, Rasmus P.
• Is Part Of: Tetrahedron letters. Volume 61:Issue 12(2020)
• Publication Date: 2020-03-19
• Subjects: Ethyl 4-bromo-1H-indole-2-carboxylate -- Amino acid protection -- Subunit selectivity -- Two-electrode voltage-clamp electrophysiology; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2020.151653
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: Novel cost-efficient and practical route of AICP synthesis. Preparation of ethyl 4-bromo-1 H -indole-2-carboxylate via Reissert indole synthesis. Diphenylmethylester as a TFA deprotectable group for amino acid protection. Selective high affinity binding of AICP to NMDA receptors. Binding to AMPA, kainate receptors and GluN3A, GluN3B, GluD2 subunits is not observed. Abstract: ( R )-2-Amino-3-(4-(2-ethylphenyl)-1 H -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.