AVL-3288 is a type I selective positive allosteric modulator of α7 nACHRs. It represents a "first-in-class" drug for the treatment of cognitive deficits in CNS disorders such as schizophrenia and potentially other diseases of cognitive impairment such as Alzheimer’s disease and ADHD. AVL-3288 was successfully tested in representative animal models of cognitive dysfunction in schizophrenia, a disease where α7 nAChR function is impaired. To date, no specific treatments for cognitive deficits in schizophrenia exist and approved therapies do not satisfactorily improve cognition. AVL-3288 is currently in human phase I trials.

Facinicline (MEM-63908 or R-4996) is a selective nicotinic alpha-7 receptor (α7nAChR) partial agonist. It also has properties of a serotonin 3 receptor antagonist. It has hydrochloride form: RG3487 (formerly MEM3454). Facinicline enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT3 receptor antagonism. It improves cognition and sensorimotor gating in rodents. It has been tested in Alzheimer's disease and cognitive symptoms of schizophrenia.

VTP-194204 (NRX 194204, IRX4204) is a second-generation retinoid X receptor (RXR) agonist that has no cross-reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. Rexinoid NRX 194204 selectively binds to and activates RXRs. Because RXRs can form heterodimers with several nuclear receptors (NRs), RXR activation by this agent may result in a broad range of gene expression depending on the effector DNA response elements activated. Rexinoid NRX 194204 may inhibit the tumour-necrosis factor (TNF)-mediated release of nitric oxide (NO) and interleukin 6 (IL6) and may inhibit tumour cell proliferation. This agent appears to be less toxic than RAR-selective ligands. VTP-194204 (IRX-4204) is in phase II clinical trials by Io Therapeutics for the treatment of prostate cancer. It is also in preclinical trials for the treatment of Alzheimer's disease, autoimmune diseases and multiple sclerosis.

Lorediplon is a novel non-benzodiazepine, the hypnotic drug acting as a GABAA receptor modulator, differentially active at the alpha1-subunit, associated with promoting sleep. As compared with other selective benzodiazepine receptor agonists, lorediplon has demonstrated in pre-clinical studies a potent hypnotic profile with potential advantages in sleep maintenance and sleep architecture preservation associated with a good safety profile, that is, no induction of tolerance, lack of next-day hangover effect, weak effect on muscular tone, and weak interaction with ethanol. Lorediplon demonstrated a minimum of 10-fold and the 6-fold increase in potency (respectively) in the spontaneous motor activation studies, compared with the currently marketed hypnotics (zolpidem and zaleplon). Additionally, when the electroencephalogram (EEG) effects of lorediplon and zolpidem were compared in the sleep-wake cycle in the mouse, lorediplon demonstrated a 10-fold increase in potency compared with zolpidem in the sleep-wake cycle and 13% greater possibility of fewer wake episodes than zolpidem. At concentrations of 1.2mg/kg, lorediplon demonstrated a 57%increased effect on Slow Wave Sleep (SWS), when compared with a placebo. In clinical trials, the clinical safety and tolerability were excellent for all doses tested. In pharmacokinetic studies, after oral administration, lorediplon is rapidly absorbed from the gastrointestinal tract reaching maximum plasma concentrations at approximately 2 h. Lorediplon demonstrated a dose-dependent improvement in sleep, whereas zolpidem showed a more sustained wake after sleep onset effect. No next-day hangover effects were observed. These sleep effects are also consistent with the pharmacokinetic profile of lorediplon.

Trichostatin A (TSA) was originally isolated as an antifungal antibiotic along with its fermentation congeners trichostatin B ((TSA)3-Fe) and the D-glucopyranosides trichostatin C and D. TSA inhibits HDAC in the low nanomolar range and is an inducer of histone hyperacetylation, both in vitro and in vivo. It inhibits all class I and II deacetylases to a similar extent in both tumor and non-tumor cells, although HDAC4 is slightly resistant when compared with HDAC1 and HDAC6. Class III HDAC is not affected by TSA. It has been shown that TSA dosedependently inhibits growth and induces apoptosis in a plethora of carcinoma cell lines in vitro. Recently, it was also found that TSA inhibits angiogenesis, which is important for the growth and metastasis of solid tumors, both in vivo and in vitro. In HT-29 colon carcinoma cells, a single dose of TSA induced transient hyperacetylation of histone H4 resulting in the induction of p21WAF1/Cip1 and inhibition of cellular proliferation at both the G1 and G2 phases of the cell cycle. Growth inhibition was associated with decreased cyclin D1 mRNA and cdk6 protein levels and increased cyclin D3 protein and p21WAF1/Cip1 mRNA levels. Cyclin D1 protein, cyclin D3 mRNA, cdk2 and cdk4 remained unaffected. In addition, TSA induced apoptosis by upregulating the expression of the pro-apoptotic genes ID1, ID2 and ID3, whereas the expression of the anti-apoptotic genes BclxL and Hsp27 was decreased In vivo, TSA induces differentiation and shows chemotherapeutic activity against N-methylnitrosureainduced rat mammary cancer without toxic side effects. TSA may also have therapeutic potential for the treatment of a variety of genetic and infectious diseases since silenced, transduced genes are reactivated probably due to structural changes of the chromatin on integrated viral sequences.

MK-212 is a 5HT2C-receptor agonist. It displays selectivity for 5-HT2C over 5-HT2A (IC50 values are 0.028 and 0.42 uM for human 5-HT2C and 5-HT2A receptors expressed in HEK293 cells respectively). A dose-dependent the effect of 5HT2C-receptor agonist MK-212 on mouse behavior was demonstrated. Intraperitoneal injection of MK-212 in high doses (0.5 and 1.0 mg/kg) increased blood level of corticosterone in mice and reduced their motor activity. In low doses of 0.1 and 0.2 mg/kg, the agonist reduced anxiety, but had no effect on motor activity. It is hypothesized that low doses of MK-212 exhibited anxiolytic activity in mice.

PF-04447943 is a potent, selective brain penetrant PDE9 inhibitor (Ki of 2.8, 4.5 and 18 nM) for human, rhesus and rat recombinant PDE9 respectively and high selectivity for PDE9 versus PDEs1-8 and 10-11. PF-04447943 was being developed by Pfizer for the treatment of cognitive disorders. PF-04447943 attenuates a scopolamine-induced deficit in a novel rodent attention task. PF-04447943 enhances synaptic plasticity and cognitive function in rodents. PF-04447943 has completed Phase II clinical trials in subjects with mild to moderate AD in 2013 but this research was discontinued. Pfizer completes a phase I trial in Sickle cell anaemia.

Parafluorofentanyl is a selective mu-opioid agonist, an analog of fentanyl, developed by Janssen. The drug was not developed for human use but is produced and abused illegally.

Buparlisib (NVP-BKM12), a dimorpholino pyrimidine derivative, is a selective pan class I phosphatidylinositol-3 kinase (PI3K) inhibitor for treating cancer. It penetrates the blood-brain barrier and has a potential as a glioma treatment. NVP-BKM120 inhibits PI3K activity by binding to the ATP binding cleft of this enzymes and was tested against class I PI3K and other kinases using an ATP depletion (Kinase-Glo) assay. The compound was shown to be active against P110 α, β, γ and δ. The inhibition of the PI3K signaling pathways leads to different forms of cell death on the basis of p53 statuses. Buparlisib demonstrated its activity in human glioblastoma (GBM) cells in vitro and in vivo and is in clinical trials for solid tumors including GBM.

MPEP (2-methyl-6-(phenylethynyl)pyridine) was one of the first compounds found to act a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. It was under development by Novartis in the late 1990's. MPEP was found to produce neuroprotective effects following acute brain injury in animals. MPEP was also found to have positive effects on animal models of depression, anxiety and morphine withdrawl.