NMDA receptors in clinical neurology: excitatory times ahead

Abstract

Since the N-methyl-D-aspartate receptor (NMDAR) subunits were cloned less than two decades ago, a substantial amount of research has been invested into understanding their physiological function in the healthy CNS. Research has also been directed at their pathological roles in various neurological diseases, including disorders resulting from acute excitotoxic insults (eg, ischaemic stroke, traumatic brain injury), diseases due to chronic neurodegeneration (eg, Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis), disorders arising from sensitisation of neurons (eg, epilepsy, neuropathic pain), and neurodevelopmental disorders associated with NMDAR hypofunction (eg, schizophrenia). Selective NMDAR antagonists have not produced positive results in clinical trials. However, there are other NMDAR-targeted therapies used in current practice that are effective for treating some neurological disorders. In this Review, we describe the evidence for the use of these therapies and provide an overview of drugs being investigated in clinical trials. We also discuss new NMDAR-targeted strategies in clinical neurology.

Figure 1

Excitatory synapse in the CNS. The excitatory neurotransmitter, glutamate, is released from presynaptic vesicles and diffuses across the synaptic cleft to act on two different types of receptors: ionotropic glutamate receptors, which have an intrinsic ion channel, and metabotropic glutamate receptors (mGluR), which are coupled to G proteins (α, β, and γ subunits). The three subtypes of ionotropic glutamate receptors include AMPA receptor (AMPAR), NMDA receptor (NMDAR), and kainate receptor (KAR).

Figure 2

Potential sites for drug action within the NMDAR protein complex. (A) Extracellular sites include the glycine (Gly) binding site on NR1 subunits, glutamate (Glu) binding site on NR2 subunits, and binding sites within the channel pore which overlap with the site for magnesium binding (Mg²⁺) (2;3). D-serine is an endogenous coagonist at the glycine binding site (7). Currently used drugs or previously tested drugs which target these sites are indicated. NR2 subunits also contain sites of action for polyamines, zinc, and protons. The site of action of NR2B selective antagonists, such as traxoprodil, overlaps with a zinc binding site on NR2B subunits (138;139). (B) Intracellular targets include signalling molecules such as kinases, phosphatases, other enzymes, and scaffold proteins which are components of the NMDAR protein complex. These molecules are upstream modulators of NMDAR function or downstream effectors of NMDAR activity.

Figure 2

Potential sites for drug action within the NMDAR protein complex. (A) Extracellular sites include the glycine (Gly) binding site on NR1 subunits, glutamate (Glu) binding site on NR2 subunits, and binding sites within the channel pore which overlap with the site for magnesium binding (Mg²⁺) (2;3). D-serine is an endogenous coagonist at the glycine binding site (7). Currently used drugs or previously tested drugs which target these sites are indicated. NR2 subunits also contain sites of action for polyamines, zinc, and protons. The site of action of NR2B selective antagonists, such as traxoprodil, overlaps with a zinc binding site on NR2B subunits (138;139). (B) Intracellular targets include signalling molecules such as kinases, phosphatases, other enzymes, and scaffold proteins which are components of the NMDAR protein complex. These molecules are upstream modulators of NMDAR function or downstream effectors of NMDAR activity.

Figure 3

Chemical structures of felbamate, riluzole, amantadine, and memantine. The structures of these chemical compounds were copied from the National Library of Medicine (NLM)/National Center for Biotechnology Information (NCBI) PubChem database site (http://pubchem.ncbi.nlm.nih.gov/).

Figure 4

Current and emerging NMDAR-based strategies for treatment of neurological diseases. These strategies include NMDAR antagonism, decreasing glutamate release by inhibiting presynaptic voltage-gated Na⁺ and/or Ca²⁺ channels, enhancing glutamate uptake from the synaptic cleft by excitatory amino acid transporter (EAAT) on neurons and glia, and targeting intracellular signalling molecules associated with synaptic or extrasynaptic NMDARs. Currently used drugs or drugs being studied (in gray italics) which target these sites are indicated.