Levomethorphan ( L-stereoisomer of racemethorphan) is an opioid analgesic of the morphinan family that has never been marketed. Levomethorphan is a methylated prodrug of levorphanol, that undergoes hepatic demethylation, converting it to the active form. Levomethorphan (via it’s active form levorphanol)functions as a potent agonist of all three of the opioid receptors, μ, κ (κ1 and κ3 but notably not κ2), and δ, as an NMDA receptor antagonist, and as a serotonin-norepinephrine reuptake inhibitor. Via activation of the KOR, levomethorphan can produce dysphoria and psychotomimetic effects such as dissociation and hallucinations. Levomethorphan is listed under the Single Convention on Narcotic Drugs 1961 and is regulated like morphine in most countries. In the United States it is a Schedule II Narcotic controlled substance.

Dexanabinol is the synthetic cannabinoid. It is inactive as a cannabimimetic, but exhibits pharmacological properties characteristic of an N-methyl-D-aspartate (NMDA)-receptor antagonist. It blocks NMDA-receptors stereospecifically by interacting with a site close to, but distinct from, that of uncompetitive NMDA-receptor antagonists and from the recognition sites of glutamate, glycine, and polyamines. This agent also scavenges peroxy radicals and protects neurons from the damages of reactive oxygen species. Furthermore, dexanabinol inhibits the activity of nuclear factor kappa B (NF-kB), thereby preventing the expression of NF-kB target genes, such as tumor necrosis factor alpha, cytokines and inducible nitric oxide synthase. Dexanabinol is a potent cerebroprotective agent, with a therapeutic window of about 4 h. Dexanabinol is safe, but is not efficacious in the treatment of traumatic brain injury. It was introduced into clinical trials for breast cancer and advanced solid tumors.

Licostinel (ACEA 1021) is a potent competitive antagonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. The robust efficacy of glycine/NMDA antagonists, such as ACEA 1021, 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. In vivo ACEA 1021 reduced the rate of propagation of cortical spreading depression, an effect consistent with blockade of NMDA receptors. ACEA 1021 also decreased audiogenic myoclonus in resuscitated rats following cardiac arrest, and the minimum alveolar concentration for halothane, effects which suggest a reduction of excitatory amino acid neurotransmission. ACEA 1021 crosses the blood-brain barrier and blocks the pathophysiologic consequences of NMDA receptor overstimulation. It was neuroprotective with a favorable therapeutic window in models of transient and permanent cerebral ischemia, epilepsy and pain.

Kynurenic acid is a product of the normal metabolism of amino acid L-tryptophan which has been shown to have a neuroactive profile. It exhibits activity against NMDA receptors and Neuronal acetylcholine receptor subunit alpha-7. It has been investigated as a potential therapeutic compound and as a biomarker in a number of neurological disorders. Although Kenyruic acid exhibits a poor penetration of the blood-brain barrier, it remains to be of particular interest to those researching Schizophrenia.

Lubeluzole is a medication, developed by Janssen Research Foundation for the treatment of acute ischemic stroke. The drug action is discussed to involve the inhibition of NMDA receptor and sodium channels.

GV 150526A (gavestinel) is an investigational drug for a neuroprotective therapy of acute ischemic stroke within 6 hours of symptom onset. It is a potent and selective non-competitive antagonist at the glycine site of the N-methyl-D-aspartate receptor (NMDA) which reduces infarct volume in experimental stroke models. Gavestinel acts at the strychnine-insensitive glycine binding site of the NMDA receptor-channel complex with nanomolar affinity (pKi = 8.5), coupled with high glutamate receptor selectivity. Gavestinel displays higher than 1000-fold selectivity over NMDA, AMPA and kainate binding sites and is orally bioavailable and active in vivo. GV 150526A inhibited convulsions induced by NMDA in mice, when administered by both IV and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The safety and efficacy of GV150526 were studied in two phase III randomized placebo-controlled clinical trials of acute ischemic stroke patients within 6 h from onset [The Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas Trials] sponsored by GlaxoSmithKline. The results of these trials suggested that gavestinel was not of substantial benefit or harm to patients with primary intracerebral hemorrhage.

Etoxadrol is an NMDA receptor antagonist. It exerts phencyclidine-like properties. Etoxadrol has anticonvulsant and anesthetic activity. Intravenous etoxadrol was clinically tested as an anesthetic.