The NMDA receptor complex: a long and winding road to therapeutics.
Advances in our basic understanding of inhibitory and excitatory amino acid neurotransmission have provided the foundation for directed drug discovery programs to modulate inhibitory GABAergic and excitatory N-methyl-D-aspartate (NMDA) receptor-mediated synapses. Gamma-Amino butyric acid (GABA(A)) and NMDA receptors are complex ion channels formed by multiple protein subunits that act as binding sites for transmitter amino acids and as allosteric regulatory binding sites to regulate ion channel activity. In the case of the NMDA receptor complex, one such allosteric site binds the obligatory glycine and/or d-serine co-agonist. Historical data from preclinical and clinical studies of GABAergic agents have clearly demonstrated that direct receptor modulators lack sufficient therapeutic indices to warrant clinical utility. However, pharmacological modulation of allosteric sites of the GABA multimeric receptor has resulted in the clinical development of safe and efficacious agents, exemplified by the benzodiazepines. Research has also revealed a similar outcome for the NMDA receptor, with allosteric modulators demonstrating improved safety profiles in the modulation of excitatory amino acid (EAA) transmission compared with direct NMDA receptor antagonists. First-generation EAA drugs were low affinity channel blockers of the NMDA multimeric receptor complex and included the anesthetic agent ketamine and the Alzheimer's drug memantine. As predicted by preclinical studies, direct NMDA receptor antagonists (eg, selfotel (Novartis AG) and high-affinity channel blockers (eg, dizocilpine) failed in the clinic as a result of narrow therapeutic indices. More recent efforts have focused on glycine/d-serine co-agonist function. These approaches include partial glycine agonists, in their agonist dose-range, for cognitive improvement and for treating schizophrenia. Such partial glycine agonists are also being advanced for the treatment of neuropathic pain in the antagonist dose range. An alternate approach to partial glycine agonists is to inhibit the uptake carrier(s) for glycine (ie, GlyT-1 and GlyT-2), thereby potentiating the lifetime of synaptic glycine. A number of glycine uptake inhibitors have been reported and their preclinical profiles support investigation into their utility in treating schizophrenia.
Wood
Paul L
PL
Northwestern University, Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering and Applied Sciences, Evanston, IL 606201, USA. p-wood@northwestern.edu
D017326:Clinical Trials, Phase III as Topic; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015394:Molecular Structure; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate