Still NAAG'ing After All These Years: The Continuing Pursuit of GCPII Inhibitors

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F16%3A00472738" target="_blank" >RIV/61388963:_____/16:00472738 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1016/bs.apha.2016.01.007" target="_blank" >http://dx.doi.org/10.1016/bs.apha.2016.01.007</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/bs.apha.2016.01.007" target="_blank" >10.1016/bs.apha.2016.01.007</a>

Result language

angličtina

Original language name

Still NAAG'ing After All These Years: The Continuing Pursuit of GCPII Inhibitors

Original language description

Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca(2+)-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was published months following the discovery of the first potent and selective GCPII inhibitor, 2-(phosphonomethyl)pentanedioc acid (2-PMPA) (Jackson et al., 1996). Over the ensuing decades, over a dozen independent laboratories used 2-PMPA and other GCPII inhibitors to elucidate two distinct neurotransmitter functions for NAAG. Under basal conditions, when GCPII activity is relatively low, intact NAAG dampens synaptic activity via presynaptic mGlu3 receptor activation and NMDA receptor blockade. However, under stimulated conditions, NAAG release and GCPII activity are enhanced resulting in excess glutamate generation, activating NMDA and other glutamate receptors, often pathologically. Diverse classes of GCPII inhibitors have been synthesized and shown to increase NAAG, decrease glutamate, and provide robust efficacy in many disease models wherein abnormal glutamatergic transmission is presumed pathogenic. In addition, over the past 20 years, basic questions regarding NAAG's synthesis, packaging into vesicles, and receptor selectivity profile have been eloquently elucidated. The purpose of this chapter is to summarize these advances and the promise of regulating NAAG metabolism through GCPII inhibition as a therapeutic strategy.

Czech name

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Czech description

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Type

C - Chapter in a specialist book

CEP classification

CC - Organic chemistry

OECD FORD branch

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Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Book/collection name

Neuropsychopharmacology: A Tribute to Joseph T. Coyle

ISBN

978-0-12-809745-8

Number of pages of the result

41

Pages from-to

215-255

Number of pages of the book

400

Publisher name

Academic Press

Place of publication

Cambridge

UT code for WoS chapter

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