Sunepitron (CP-93,393) is an anxiolytic drug with highly selective serotonin 5-hydroxytryptamine 1A autoreceptor agonist, alpha2-adrenergic antagonist, and dopamine D2 agonist properties. Sunepitron hydrochloride had been in Phase III clinical trials by Pfizer for the treatment of anxiety disorder and depression. However, this research has been discontinued.

Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. Basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy. Basimglurant is being under development by Roche for the treatment of treatment-resistant depression (as an adjunct). It is in phase II clinical trials for this indication.

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.

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.

Gaboxadol (or THIP) is a direct GABA mimetic ligand at delta-containing receptors. Gaboxadol went into human clinical trials to test if the drug promoted sleep. It was generally well tolerated. Gaboxadol enhances delta power in NREM sleep in humans. Gaboxadol failed in Phase III for sleep studies. The side effects of Gaboxadol have been described as mild and similar in quality to those of other GABA-mimetics. Gaboxadol is in development with Ovid Therapeutics as a treatment for Angelman syndrome, fragile X syndrome and epilepsy.

Rapastinel (formerly known as GLYX-13) is an investigational intravenous formulation of a novel NMDA receptor partial agonist, which is being evaluated for adjunctive treatment of Major depressive disorder, and has shown a rapid onset of antidepressant efficacy 1 day after a single dose in a Phase 2 clinical trial of patients with Major depressive disorder who had an inadequate response to one or more antidepressants. No psychotomimetic or hallucinogenic side effects were observed with rapastinel. Few adverse events were reported by 5% or more of subjects and these were rated as mild or moderate. These included headache, somnolence, dizziness, dysgeusia, and fatigue. On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received Breakthrough Therapy designation from the U.S. FDA for adjunctive treatment of major depressive disorder.

Gaboxadol (or THIP) is a direct GABA mimetic ligand at delta-containing receptors. Gaboxadol went into human clinical trials to test if the drug promoted sleep. It was generally well tolerated. Gaboxadol enhances delta power in NREM sleep in humans. Gaboxadol failed in Phase III for sleep studies. The side effects of Gaboxadol have been described as mild and similar in quality to those of other GABA-mimetics. Gaboxadol is in development with Ovid Therapeutics as a treatment for Angelman syndrome, fragile X syndrome and epilepsy.

Lanicemine is a low-trapping NMDA channel blocker, which was developed by Fisons Pharmaceuticals and later by AstraZeneca for the treatment of the major depressive disorder. The development was terminated in phase II as the drug did not meet the primary endpoint.

Radafaxine (GW353162, ( )-(2S,3S)-2-(3-chlorophenyl-3,5,5-trimethyl-2-morphinol) or S,S-hydroxybupropion) is an active metabolite of bupropion. It acts as an inhibitor of the dopamine transporter. Radafaxine was investigated for the treatment of depression however, development was discontinued.

Amibegron (SR 58611A or SR 58611) is a highly selective agonist for atypical beta3-adrenoceptors. It stimulates neuronal activity in a specific area of the prefrontal cortex and also inhibits intestinal motility. Amibegron was in phase III trials worldwide for the treatment of depression and generalised anxiety disorder but development of the product was discontinued in 2008. Amibegron has been tested for its potential as a treatment for irritable bowel syndrome.