FENPIPALONE is an oxazolidinone derivative with central nervous system depressant and antiinflammatory activity in animal models. However, FENPIPALONE did not demonstrate any usefulness for severely ill chronic schizophrenic patients.

LY2886721 is a BACE inhibitor used for the treatment of Alzheimer's Disease. LY2886721 did not inhibit other aspartyl proteases such as cathepsin D, pepsin, and renin, and reduced Aβ in a dose-dependent manner in HEK293Swe cells and in primary neurons from PDAPP transgenic mice. LY2886721 was the first BACE inhibitor to reach Phase 2 clinical research. Lilly completed six Phase 1 studies of LY2886721’s safety, tolerability, and pharmacology in a total of 150 healthy volunteers and people with Alzheimer’s disease at doses of 1–70 mg. Single and multiple ascending oral dosing was accompanied by repeat CSF sampling in the hours and days thereafter. This was done to assess CSF penetration and target engagement by way of measuring levels of the drug, BACE1 substrate, and BACE1 cleavage products. The compound lowered CSF Aβ40, Aβ42, and sAPPβ concentrations while increasing sAPPα, consistent with expectations for BACE1 inhibition. Fourteen days of daily dosing reduced BACE1 activity by 50–75 percent, and CSF Aβ42 by 72 percent. No safety concerns were apparent in dosing up to six weeks

Salvinorin A has been reported to be the most potent naturally occurring hallucinogen, with an effective dose in humans in the 200- to the 1,000-μg range when smoked; it has been reported to induce an intense hallucinatory experience in humans, with a typical duration of action being several minutes to an hour or so. Salvinorin A is a highly selective agonist of the kappa-opioid receptor (KOR) with few off-target effects. It is a potent and selective dilator of the cerebral vasculature, exhibits rapid penetration through the blood-brain barrier, has potent anti-inflammatory properties, and has the ability to preserve neurovascular unit integrity. As such, salvinorin A is an ideal compound for the prevention and treatment of cerebral vasospasm following subarachnoid hemorrhage.

Sepranolone (UC1010) is a GABA-A modulating steroid antagonist (GAMSA) and does not antagonize the effect of GABA itself or other GABAA agonists like benzodiazepines and barbiturates. The interaction of neuroactive steroids (i.e., allopregnanolone and Sepranolone) with GABA-A receptor is particularly important in mood disorders. For example, allopregnanolone administration decreased saccadic eye velocity in healthy female volunteers and induced sedation and these effects were diminished by simultaneous sepranolone administration. Thus, allopregnanolone effects are antagonized by its isomer sepranolone. UC1010 reduces symptom severity and impairment significantly more efficiently than placebo in women with a well-defined, pure premenstrual dysphoric disorder. No severe adverse events were reported during the UC1010 treatment and safety parameters (vital signs and blood chemistry) remained normal during the study. It was revealed also that increases in ring A-reduced progesterone metabolites, particularly Sepranolone, are associated with chronic fatigue syndrome.

Dexmecamylamine (TC-5214, also known, as S isomer of mecamylamine) is a positive allosteric modulator of α4β2 neuronal nicotinic receptors, rather than an open-channel blocker. It was evaluated as a potential adjunct treatment for patients with major depressive disorder (MDD). TC-5214 was generally well tolerated, however, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy. The Phase 2b clinical trial of TC-5214 for the treatment for overactive bladder (OAB) revealed the high dose of TC-5214 demonstrated mixed results on the co-primary endpoints by providing a statistically significant reduction in micturition frequency and an improvement that did not reach statistical significance on episodes of urinary incontinence. As a consequence of these results, this drug was discontinuing further development of TC-5214 in OAB. The study for using TC-5214 in patients with refractory hypertension was also terminated.

GlaxoSmithKline is developing GSK-356278 as a selective, brain-penetrant phosphodiesterase 4 (PDE4) inhibitor that demonstrates anxiolytic and cognition-enhancing effects. Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. The drug was studied for the treatment of Huntington's disease, depressive and anxiety disorders. GSK-356278 has completed phase I clinical trials for evaluation of the safety, tolerability, and pharmacokinetics in male volunteers with the therapeutic dose for future clinical development.

T-2000 is an oxopyrimidine derivative patented by Taro Pharmaceutical Industries Ltd. as a tranquilizing agent. T-2000 acts as a modulator of GABA A receptor with well-documented anticonvulsant activity and little sedation in animal models. In vitro, equimolar concentrations of T-2000 and phenobarbital produce equivalent enhancement of GABA-evoked chloride currents. Unfortunately, in clinical trials T-2000 failed to demonstrate efficacy in older patients with essential tremor. Moreover, daily administration of T2000 resulted in higher total blood barbiturate levels, likely accounting for the poor tolerability.

O-Desmethyl tramadol (O-Desmethyltramadol, O-DSMT) is a metabolite of tramadol. O-Desmethyltramadol is an opioid analgesic and the main active metabolite of tramadol. (+)-O-Desmethyltramadol is the most important metabolite of tramadol produced in the liver after tramadol is consumed. This metabolite is considerably more potent as a μ-opioid agonist than the parent compound. O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in xenopus oocytes. O-desmethyl tramadol inhibits functions of M(1) receptors but has little effect on those of M(3) receptors. O-desmethyl tramadol has been widely used clinically and has analgesic activity.

NGX267 is a partial muscarinic receptor agonist with functionally specific M1 and M3 receptor activity, developed by Torrey Pines Therapeutics(TPTX) for the treatment of Xerostomia, Alzheimer’s disease and cognitive deficits in schizophrenia. NGX-267 had been in phase II clinical trials for the treatment of Xerostomia, however, all researchers on this drug candidate were discontinued.

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.