Puromycin dihydrochloride belongs to the aminonucleoside family of antibiotics and is isolated from Streptomyces alboniger. Since the partial structure of this antibiotic showed it to be a purine derivative, puromycin was assigned as its generic name. Puromycin is a broad spectrum antibiotic and antibacterial agent. It is active against Gram-positive microorganisms, less active against acid-fast bacilli, and weakly active against Gram-negative microorganisms. It acts very quickly and can kill 99% of the cells within 2 days. It also exhibits antitumor activity in studies on brain tumor cells. Puromycin is a protein synthesis inhibitor that causes premature chain termination by acting as an analog of the 3’-terminal end of aminoacyl-tRNA. It has been used to study transcriptional regulatory mechanisms that control the sequential and coordinate expression of genes during cell differentiation.

Dexoxadrol is a sigma receptor agonist. Dexoxadrol, the D-isomer of dioxodrol, which produces PCP-like behavioural effects and displaces bound [3H]PCP, was a potent blocker of the PCP-sensitive, voltage-gated K+ channel. Dexoxadrol was developed as analgesics for use in humans, however, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol. Dexoxadrol is a NMDA receptor antagonist, which possesses high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel.

Clorgiline is a monoamine oxidase (MAO) inhibitor. Specifically, it is an irreversible and selective inhibitor of MAO-A. Clorgiline was under investigation for antidepressant and anxiolytic potential but has never been marketed, likely due to efficacy concerns. It continues to see routine use as a molecular probe in biomedical research examining a number of neurological disease and cancer models. In addition to inhibiting the MAO-A receptor, it has also been found to bind to the sigma1 receptor, and with high affinity to the I2 imidazoline receptor.

Fusaric acid (J-butylpicolinic acid) is a fungal toxin with low to moderate toxicity synthesized by some Fusurium species which cause infections in cereal grains and other agricultural commodities. It may potentiate the effects of other Fusurium toxins. Fusaric acid is a potent inhibitor of DNA synthesis. Fusaric acid has potent anti-proliferative activity in vitro on various normal and cancer cell lines and suggest that it exhibits some cytotoxic specificity for growing and confluent colorectal adenocarcinoma and mammary adenocarcinoma cell lines. Fusaric acid is known as a potent dopamine-beta-hydroxylase inhibitor of high specificity. Fusaric acid calcium salt elicited the hypotensive response primarily through the reduction of total peripheral vascular resistance index.

Tetrahydrouridine is a potent competitive reversible inhibitor of cytidine deaminase. Tetrahydrouridine can inhibit cell proliferation by regulation of the cell cycle independent of cytidine deaminase (CDA) expression levels. Tetrahydrouridine may be useful for researching potential treatments for high CDA-expressing tumors. Tetrahydrouridine use, alone or in combination with the DNA methyltransferase inhibitor 5-fluoro-2’-deoxycytidine, is being evaluated in animal models and clinical trials for diseases, including cancer and mitochondrial DNA depletion syndrome.

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.

Brofoxine is an anxiolytic, useful in the treatment of psychosis.

Temefos (Diphos, Temephos) is an organophosphate larvicide, used to treat water infested with disease-carrying insects including mosquitoes, midges, and black fly larvae. Temefos affects the central nervous system through inhibition of cholinesterase, results in death before reaching the adult stage. Diphos has been used in trials studying the treatment of Plasmodium Falciparum Malaria. Temephos was first registered in the United States in 1965 by American Cyanamid Company for a number of uses including citrus fruits, pet collars, and mosquito control. A Registration Standard was issued in August, 1981. In response to EPA's 1991 Data Call-In, American Cyanamid dropped all uses except the mosquito larvicide use in non-potable waters and requested a low volume minor use waiver for relief from the data requirements associated with that use.

Growth hormone releasing hexapeptide (GHRP-6) is a synthetic met-enkephalin analog that induces the release of growth hormone in vivo through binding of the ghrelin receptor. GHRP-6 increases proliferation in astrocytes through a mechanism that involves PI3K/Akt signaling. GHRP-6 also inhibits development of restraint stress-induced gastric lesions and reverses ovariectomy-induced effects on serum glucose and insulin levels. Additionally, GHRP-6 decreases locomotor activity and increases food intake in vivo. Essentially a synthetic version of ghrelin analogue, GHRP-6 (like GHRP-2) stimulates the release of an endogenous growth hormone (GH) within the somatotropes of the anterior pituitary in the animal and human body. Specifically, GHRP-6 will increase the number of somatotropes in a GH pulse by limiting the amount of somatostatin present, while standard GHRH increases the amplitude at which the pituitary cells pulse. Unlike ghrelin, GHRP-6 is not specifically used to increase appetite, but it may have secondary actions that impact hypothalamic neurons. These effects last for approximately an hour after the initial application, which mimics the natural application of GH, and consists of an eight hour circulation period. In studies GHRP-6 has shown biological actions similar to the naturally occurring hunger stimulating peptide ghrelin. Its main use is to promote food intake by stimulating hunger and aid in energy metabolism. It can be used in the treatment of GH deficiency as well as cachexia, eating disorders and obesity. GHRP-6 is a synthetic met-enkephalin (a naturally occurring opioid growth factor) analog. GHRP-6 contains D-amino acids that are entirely synthetic, lacks opioid activity, and shares no sequence relation with GHRH. It has also been shown that GHRP-6 can lead to re-stimulation of the natural production of HGH. Studies have shown that GHRP-6 increases the secretion of IGF-1 (InsulinLike Growth Factor 1) by the liver, which is speculated to be a required component in the anabolic mechanisms leading to the action of HGH. It also appears that GHRP-6 has positive implications for the central nervous system, as ghrelin is known to protect neurons.

BN-82451 belongs to a family of small molecules designated as multitargeting or hybrid molecules. BN-82451 is orally active, has good central nervous system penetration, and elicits potent neuronal protection and antiinflammatory properties. BN-82451 acts via three major pathways involved in neuronal death: excito-toxicity, oxidative stress, and inflammation, and is also a mitochondrial protective agent. Because BN-82451 is a multitargeting agent, each of its specific sites of action has been extensively evaluated, namely, neuronal excitotoxicity (sodium channel blocker), oxida-tive stress (antioxidant), neuroinflammation (cyclooxygenase inhibitor), and mitochondrialdysfunction (mitochondria-protective properties). BN-82451 was found to exert a significant protection in experimental animal models mimicking aspects of cerebral ischemia, Parkinson disease, Huntington disease, and more particularly amyotrophic lateral sclerosis. BN-82451 is in phase II clinical trials by Ipsen Pharma for the treatment of Huntington’s disease. In 2015, orphan drug designation was assigned in the U.S. to the compound for the indication.