Chlordiazepoxide (trade name Librium) is a sedative and hypnotic medication of the benzodiazepine class. Chlordiazepoxide is indicated for the management of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of Librium in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. Chlordiazepoxide acts on benzodiazepine allosteric sites that are part of the GABAA receptor/ion-channel complex and this results in an increased binding of the inhibitory neurotransmitter GABA to the GABAA receptor thereby producing inhibitory effects on the central nervous system and body similar to the effects of other benzodiazepines. Chlordiazepoxide act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in animal nerve terminal preparations. The withdrawal of chlordiazepoxide during pregnancy and breastfeeding is recommended, as chlordiazepoxide rapidly crosses the placenta and also is excreted in breast milk. Chlordiazepoxide is a long-acting benzodiazepine drug. The half-life of Chlordiazepoxide is 5 – 30 hours but has an active benzodiazepine metabolite (desmethyldiazepam), which has a half-life of 36 – 200 hours. The necessity of discontinuing therapy because of undesirable effects has been rare. Drowsiness, ataxia and confusion have been reported in some patients — particularly the elderly and debilitated. While these effects can be avoided in almost all instances by proper dosage adjustment, they have occasionally been observed at the lower dosage ranges. In a few instances syncope has been reported.

Coluracetam (code name BCI-540; formerly MKC-231) is a nootropic agent of the racetam family. It was initially developed and tested by the Mitsubishi Tanabe Pharma Corporation for Alzheimer's disease. After the drug failed to reach endpoints in its clinical trials it was in-licensed by BrainCells Inc for investigations into major depressive disorder (MDD). Like most racetam compounds, Coluracetam increases choline uptake, but it also increases uptake in damaged neurons. Specifically, Coluracetam interacts with the HACU process, which is responsible for absorbing choline into the neurons. This increased uptake occurs during the Acetylcholine synthesis process. Since Coluracetam improves choline preservation during this process, a larger amount is converted into Acetylcholine. This results in increased memory, attention and alertness. It is important to note here, that these benefits were only seen in subjects with previously impaired neurons, not in subjects with normally functioning neurons. Coluracetam is also shown to improve AMPA potentiation, which is a process that triggers cognitive function and alertness. Although Coluracetam interacts with choline transporters as well, there isn’t enough evidence to explain why or how this interaction occurs, or what occurs after the interaction. Coluracetam has been in phase II clinical trials for the treatment of major depression and anxiety. However, this research has been 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.

Siramesine is a sigma2 opioid agonist under development by H Lundbeck as a potential treatment for anxiety. In March 1998, the compound was licensed to Forest Laboratories under a strategic alliance. In August 2000, siramesine entered phase II trials. Siramesine has been shown to trigger cell death of cancer cells and to exhibit a potent anticancer activity in vivo. Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes. Siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation. Siramesine involves lysosomal leakage and oxidative stress.

Traxoprodil (CP-101,606) is a potent, selective N-Methyl-D-aspartate (NMDA) receptor (NR2B subunit) antagonist under development by Pfizer for its potential as a neuroprotectant in head injury and neurodegenerative disease. It is in phase II trials in the US and in phase I in Japan for the potential treatment of head injury, such as, Depressive Disorder, Major and Parkinson's Disease. CP-101,606 does not protect against glutamate-induced neurotoxicity in cultured cerebellar neurons, up to a dose of 10 uM. These results are consistent with CP-101,606 being a potent NMDA antagonist, selective for the type of NMDA receptor associated with the hippocampus. Some further investigation revealed that CP-101,606 was associated with a dose-related dissociation and amnesia. These results support the hypothesis that glutamate antagonists may be useful antidyskinetic agents. However, future studies will have to determine if the benefits of dyskinesia suppression can be achieved without adverse cognitive effects.

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.

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.

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.

Idazoxan is an alpha2 receptor antagonist which also shows activity at imidazoline I1 and I2 receptors and modulates the release of dopamine. Idazoxan was in phase II development in the US. Later the development of idazoxan for schizophrenia was discontinued. It was also in clinical trials for cognition disorders in United Kingdom, and was also discontinued. Idazoxan is used in scientific research as a tool for the study of alpha 2-adrenoceptors.

ADX-71149 (JNJ-40411813), a phenylpiperidine-substituted pyridone, is positive allosteric modulator (PAM) metabotropic glutamate type 2 (mGlu2) receptor activity. In fed rats, JNJ-40411813 was rapidly absorbed with an absolute oral bioavailability of 31%. ADX-71149 (JNJ-40411813) demonstrates antipsychotic activity in vivo rodents experiments. ADX-71149 (JNJ-40411813) is being jointly developed by Addex Therapeutics and Janssen Pharmaceuticals, a Johnson & Johnson company, for the treatment of epilepsy. Addex Therapeutics was also developing the candidate for schizophrenia, major depressive disorder and anxiety disorders. However, development in these indications has been discontinued.