Glycine/NMDA Receptor Antagonists as Potential CNS Therapeutic Agents: ACEA-1021 and Related Compounds

Abstract

Glutamate is the main excitatory neurotransmitter in central nervous system (CNS) and NMDA receptors are one of the major classes of ionotropic glutamate receptors. NMDA receptors have been known to play critical roles in normal CNS activities, as well as in many pathological conditions, including both acute and chronic diseases. The discovery of glycine as a coagonist of NMDA receptors has led to intensive research of glycine/NMDA antagonists as potential CNS drugs. The robust efficacy of glycine/NMDA antagonists, such as ACEA-1021 (5), in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA-1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. However, through SAR studies, compounds such as ACEA-1416 (10) have been identified with improved properties, such as higher in vivo potency and site for potential metabolism. Therefore these compounds should be able to overcome some of the liabilities of ACEA-1021 and potentially could be developed as neuroprotectants. Based on the preclinical and clinical studies of glycine/NMDA antagonists, as well as the clinical experiences with t-PA, initiation of treatment within a short time window after the onset of stroke could be critical for the success of these antagonists in clinical trials. This can be accomplished by implementing the procedure developed for t-PA clinical trials, with modification based on the safety profile of glycine/NMDA antagonists, for future clinical trial to administer the drug as soon as possible after stroke onset. In addition, glycine/NMDA antagonists also have other potential therapeutic applications, such as for the treatment of traumatic brain injury, pain, cocaine overdose and convulsions.

Neuroprotection targets after traumatic brain injury

“…These second-generation memantine-derivative therapeutics were designed to be activated under pathologically conditions and, in preliminary studies, appear to offer better neuroprotection [17 ]. Traxoprodil (CP-101606) antagonist is highly selective for the NR2B subunit of the NMDA receptor [18]; ACEA-1416, an analog of ACEA-1021 [19], and arcaine, an analog of agmatine [20], have been shown to be neuroprotective in animal models of brain injury and ischemia, and appear to better tolerated. a-Amino-3-hydroxy-methyl-4-isoxazolylpropionic acid receptor antagonists…”

Neuroprotective Mechanisms of Lycium barbarum Polysaccharides Against Ischemic Insults by Regulating NR2B and NR2A Containing NMDA Receptor Signaling Pathways

“…Excess release of glutamate from presynaptic membranes induced by ischemia overactivates glutamate receptors leading to a series of events including intracellular calcium overload, excessive ROS production and mitochondrial stress and finally neuronal death (Benveniste et al, 1984 ; Lipton and Rosenberg, 1994 ). However, based on accumulating evidence in the literature, all clinical trials using glutamate receptor inhibitors have failed (Koh and Choi, 1991 ; Morris et al, 1999 ; Albers et al, 2001 ; Ikonomidou and Turski, 2002 ) although some of the inhibitors reduced ischemic damage in animal experiments (Lin et al, 1993 ; Reyes et al, 1998 ; Cai, 2006 ). It is known that glutamate receptors play important roles in maintaining physiological functions such as excitatory signal transduction, learning and memory (Mayer and Westbrook, 1987 ; Newcomer et al, 2000 ).…”

Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme

“…Of various subunits and their combinations, glycine can bind to GluN1 and GluN3 subunits1112 with pharmacological and structural differences in both binding sites1314. More importantly, it has been suggested that the glycine binding site of GluN1 is a potential pharmacological target for treating PD, schizophrenia, traumatic brain injury, and anxiety15161718.…”