Molecular mechanisms underlying the N-methyl-d-aspartate receptor antagonists: Highlighting their potential for transdiagnostic therapeutics

Abstract

The so-called "psychedelic renaissance" has stimulated expanded interest in several classes of drugs that appear to possess transdiagnostic effects in the treatment of mental health disorders, specifically. N-methyl-d-aspartate receptor (NMDAR) antagonists are one such class with diverse therapeutic potential. NMDARs mediate excitatory postsynaptic signalling in the central nervous system (CNS) and are integral to normal neurobiological processes including neuronal development, synaptic transmission, and plasticity, and thus involved in learning and memory. However, NMDAR hyper-function is also implicated in acute CNS trauma, neuropsychiatric and neurodegenerative disorders, as well as chronic pain. The complex structure of NMDARs permits several locations for therapeutic inhibition, making these receptors a potential target for multiple drugs which modulate them in different ways. NMDAR antagonists, which may be competitive, non-competitive, or uncompetitive, either block glutamate from binding the receptor or modulate the response to glutamate binding. Despite longstanding concerns about side effects of NMDAR antagonists, recent research suggests that, when appropriately used, these agents have favourable safety profiles. Furthermore, their fast-acting mechanism of action, resulting in rapid effects compared to other therapeutic agents, makes them a promising class of drugs that may yield effective therapeutics for multiple CNS disorders.

Keywords: CNS disorders; Ketamine; Memantine; Mental disorders; NMDAR antagonists.