Competitive Gly/NMDA Receptor Antagonists

Abstract

Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischemia, epilepsy, amiotrophic lateral sclerosis (ALS), Parkinson's and Alzheimer's diseases. In addition to the classical competitive glutamate receptor (GluR) antagonists, much effort has been directed toward the development of many different non-competitive antagonists of these receptors and, among them, compounds blocking the glycine site on the NMDA receptor complex (Gly/NMDA) have been widely investigated. Many Gly/NMDA receptor antagonists showed to be potential therapeutic agents in many neurological diseases such as stroke, epilepsy and neuropathic pain. Some of them, endowed also with favourable physicochemical properties and low secondary undesiderable effects, reached clinical trials.

Synthesis and Biological Evaluation of a New Set of Pyrazolo[1,5-c]quinazolines as Glycine/N-Methyl-D-aspartic Acid Receptor Antagonists

“…This was unexpected because up to now the presence at position-2 of a substituent able to engage either a hydrogen-bond or a lipophylic interaction with the receptor sites was thought to be an important structural requirement for the anchoring of PQZ derivatives at the three receptor types. 15,30) It has to be noted that binding affinities at glycine/NMDA, AMPA and KA receptors of the 2-unsubstituted-1-carboxylic acid 10 are comparable to those of its corresponding 1-unsubstituted-2-carboxylic acid C. 21) This finding represents a novelty and indicates that the position of the carboxylate group in the upper region of the PQZ scaffold does not affect anchoring at the receptor sites.…”

“…In addition, glycine/NMDA receptor antagonists have other potential therapeutic applications, such as for the treatment of traumatic brain injury, chronic pain, drug and alcohol abuse and tolerance. [6][7][8][9][10][11][12][13][14][15] Over the past decade, our laboratory has been notably involved in the elucidation of the structure-activity relationship (SAR) of different chemical classes of heterocyclic compounds acting as glycine/NMDA and/or AMPA and/ or KA receptor antagonists. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] One of these classes is represented by the 8-chloro-5,6-dihydro-5-oxo-pyrazolo [1,5-c]quinazoline-2-carboxylates (PQZ series) ( Fig.…”

“…It has to be noted that 1-6 bear a lipophilic amide side chain similarly to a number of bicyclic or tricyclic heteroaromatic derivatives reported as potent and selective glycine/NMDA receptor antagonists. 15) Moreover, the glycine/NMDA receptor pharmacophore model reported in the literature 15,30) shows a hydrophobic pocket that well accommodates bulky groups in a region of the receptor site corresponding to position-2 of the PQZ scaffold.…”

Pyrazoloquinazolines: Synthetic strategies and bioactivities

“…Varano and his research group reported the AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid) [40,41], Gly/NMDA (Glycine/N-methyl-D-aspartic acid) [42] and KA (kainic acid) [43] receptor binding affinity of 1,9-disubstituted-8-chloro-6a, 7,8,9,10, presence of carboxyl groups at position-1 and 2 which due to its electrostatic interactions between negatively charged carboxylate group and positively charged site on receptors increased the affinity of 23. Compound 25 showed highest affinity towards AMPA receptor whereas compound 26 exhibited highest affinity toward Gly/NMDA receptor.…”

Synthesis of 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides and their evaluation as ligands for NMDA receptor glycine binding site

“…The presence of a co-agonist, which binds to a specific strychnine-insensitive glycine binding site (glycine B) of the NMDA receptor, is necessary for ion channel activity 5 . Therefore, the glycine binding site was perceived as a unique pharmacological target and several highly potent glycine binding site antagonists have been discovered [6][7][8] . As, unsurprisingly, glycine B antagonist pharmacophore 9 does not look like a brain penetrant, this was one of the reasons for low efficacy in vivo.…”