Dextromethorphan is a non-narcotic morphine derivative widely used as an antitussive for almost 40 years. It has attracted attention due to its anticonvulsant and neuroprotective properties. It is a cough suppressant in many over-the-counter cold and cough medicines. In 2010, the FDA approved the combination product dextromethorphan/quinidine for the treatment of pseudobulbar affect. Dextromethorphan suppresses the cough reflex by a direct action on the cough center in the medulla of the brain. Dextromethorphan shows high-affinity binding to several regions of the brain, including the medullary cough center. This compound is an NMDA receptor antagonist and acts as a non-competitive channel blocker. It is one of the widely used antitussives and is used to study the involvement of glutamate receptors in neurotoxicity. Dextromethorphan (DM) is a sigma-1 receptor agonist and an uncompetitive NMDA receptor antagonist. The mechanism by which dextromethorphan exerts therapeutic effects in patients with pseudobulbar affect is unknown. Dextromethorphan should not be taken with monoamine oxidase inhibitors due to the potential for serotonin syndrome. Dextromethorphan is extensively metabolized by CYP2D6 to dextrorphan, which is rapidly glucuronidated and unable to cross the blood-brain barrier.

Cutamesine, an agonsit of brain sigma 1 receptors, was developed by Santen Pharmaceutical for the treatment of cognitive diseases. The drug was tested in phase II in patients with major depressive disorders and for recovery of patients with stroke, however its development was terminated for the given conditions. Currently M's science corporation is developing cutamesine for Amyotrophic lateral sclerosis and Retinitis pigmentosa as more suitable target diseases.

Rimcazole is a carbazole derivative that acts as a sigma receptor antagonist and studied as potential antipsychotic agent for the treatment of acute schizophrenic patients. In open-clinical trials Rimcazole (BW 234U) appears to be effective in acute schizophrenic patients. However, subsequent clinical trials demonstrated that rimcazole lacked efficacy in schizophrenic patients and it is now primarily used as an experimental tool. In addition to its actions as  receptor antagonist, rimcazole also has high affinity for dopamine transporters, and inrecent years it has served as a lead compound for the development of novel dopamine transporter ligands.

ANAVEX 2-73 is an orally available drug candidate developed to potentially modify Alzheimer’s. This drug is in Phase II trials for Alzheimer's disease and Rett syndrome, phase I trials for epilepsy and in preclinical trials for multiple sclerosis and Parkinson's disease. ANAVEX 2-73 is a sigma-1 receptor agonist, which also has micromolar affinities for muscarinic M1–M4 receptors, the sodium channel site 2 and NMDAreceptors. Observed adverse events at doses above the maximum tolerated single dose (60 mg) included headache and dizziness, which were moderate in severity and reversible.

Dextrorphan is an active metabolite of dextromethorphan, is an antitussive agent, which was found in cough medicines. Dextrorphan is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, sigma 1 receptor agonist, so as is an agonist of mu and kappa opioid receptors. In addition was found, that dextrorphan possessed anticonvulsive and neuroprotective effects.

Igmesine is a sigma-1 receptor agonist. It was assayed in clinical trials targeting major depressive disorder. Igmesine is the only antisecretory agent that we have tested to date that inhibits both cholera toxin and the E. coli enterotoxins. Sigma receptors are known to be present on nerves in the enteric nervous system and this would seem to be a potentially useful class of drugs to pursue for the treatment of secretory diarrhoea in humans. It was shown that when Alzheimer's disease rats were submitted to the conditioned fear stress test, igmesine can significantly reduce the stress-induced motor suppression, indicating exogenous σ-1 receptor agonists may alleviate Alzheimer's disease-associated depressive symptoms.

Orvepitant is a novel generation brain penetrant, selective and potent, small molecule NK-1 receptor antagonist. Orvepitant’s (GW823296) mode of action and developability characteristics made it a suitable development candidate for the treatment of common anxiety disorders, posttraumatic stress disorder and major depressive disorder. It’s in phase II clinical trials as an effective inhibitor of itch-associated response.

Pridopidine is an experimental drug candidate belonging to a class of agents known as dopidines, which act as dopaminergic stabilizers in the central nervous system. As a dopamine stabilizer, pridopidine is thought to reduce the effects of dopamine when there’s too much and increase its effects when there’s too little. Pridopidine, therefore, plays two opposing roles in the brain, which stabilize dopamine levels. In this way, pridopidine is thought to help the brain reestablish a normal balance of neurotransmitters, and thus regain control over motion. Pridopidine intended to treat Huntington’s disease movement symptoms. Pridopidine was well tolerated and had an adverse event profile similar to a placebo.

Esaprazole, also known as hexaprazole, was developed in the 1980s as a drug for the treatment of gastric and duodenal ulcers. Esaprazole exerts a dose-dependent cytoprotective effect on the gastric mucosa in man. It was shown to have a dose-dependent antisecretory activity, which was particularly evident on secretion volume and acid output. Esaprazole completed phase II clinical trials with only a few minor side effects being reported, but was shown to be less effective than Cimetidine and Ranitidine at healing ulcers. Esaprazole is a weak sigma opioid receptor and muscarinic acetylcholine receptors M3 and M5 ligand. Esaprazole analogs with many compounds showing neuroprotective properties.

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.