Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).
Vasopressin V1b receptor (V1BR) also known as vasopressin 3 receptor (VPR3) or antidiuretic hormone receptor 1B is a protein that in humans is encoded by the AVPR1B gene.
The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin. In humans, the oxytocin receptor is encoded by the OXTR gene which has been localized to human chromosome 3p25.
Gepirone is an antidepressant and anxiolytic drug of the azapirone group that was synthesized by Bristol-Myers Squibb in 1986 and has been under development for the treatment of depression but has yet to be marketed. It has been under development in the U.S. in an extended release form, but despite completing phase III clinical trials and demonstrating efficacy, it has been rejected multiple times by the Food and Drug Administration (FDA) during the drug approval process. However, in March 2016, the FDA reversed course and ruled favorably on the efficacy of gepirone.
Nelivaptan (INN) is a selective, orally active, non-peptide vasopressin receptor antagonist selective for the V1B subtype. The drug had entered clinical trials for treatment of anxiety and depression. In July 2008, Sanofi-Aventis announced that further development of this drug had been halted.
Selfotel (CGS-19755) is a drug which acts as a competitive NMDA antagonist, directly competing with glutamate for binding to the receptor. Initial studies showed it to have anticonvulsant, anxiolytic, analgesic and neuroprotective effects, and it was originally researched for the treatment of stroke, but subsequent animal and human studies showed phencyclidine-like effects, as well as limited efficacy and evidence for possible neurotoxicity under some conditions, and so clinical development was ultimately discontinued.
SB-258585 is a drug which is used in scientific research. It acts as a potent, selective and orally active 5-HT6 receptor antagonist, with a Ki of 8.9nM. It is used in its 125I radiolabelled form to map the distribution of 5-HT6 receptors in the brain.
Lixivaptan (VPA-985) is an orally-active, non-peptide, selective vasopressin 2 receptor antagonist being developed as an investigational drug by Palladio Biosciences, Inc. (Palladio), a subsidiary of Centessa Pharmaceuticals plc. As of December 2021, lixivaptan is in Phase III clinical development for the treatment of Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease. The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to lixivaptan for the treatment of ADPKD.
Vestipitant (INN) is a drug developed by GlaxoSmithKline which acts as a selective antagonist for the NK1 receptor. It is under development as a potential antiemetic and anxiolytic drug, and as a treatment for tinnitus and insomnia.
A serenic, or antiaggressive agent, is a type of drug which reduces the capacity for irritability and aggression.
WAY-267464 is a potent, selective, non-peptide agonist for the oxytocin receptor, with negligible affinity for the vasopressin receptors. Contradictorily however, though originally described as selective for the oxytocin receptor and lacking affinity for the vasopressin receptors, it has since been reported to also act as a potent vasopressin V1A receptor antagonist. WAY-267464 has been shown to cross the blood-brain-barrier to a significantly greater extent than exogenously applied oxytocin, and in animal tests produces centrally-mediated oxytocinergic actions such as anxiolytic effects, but with no antidepressant effect evident. It was developed by a team at Ferring Pharmaceuticals.
An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one or both of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.
Aticaprant, also known by its developmental codes JNJ-67953964, CERC-501, and LY-2456302, is a κ-opioid receptor (KOR) antagonist which is under development for the treatment of major depressive disorder. A regulatory application for approval of the medication is expected to be submitted by 2025. Aticaprant is taken by mouth.
Balovaptan, is a selective small molecule antagonist of the vasopressin V1A receptor which is under development by Roche for the treatment of autism. As of August 2019, it is in a phase III clinical trial for adults and a phase II clinical trial for children for this indication. On 29 January 2018, Roche announced that the US Food and Drug Administration (FDA) had granted Breakthrough Therapy Designation for balovaptan in individuals with autism spectrum disorder (ASD). The FDA granted this based on the results of the adult phase II clinical trial called VANILLA study. The currently-recruiting phase III adult study is called V1aduct and the currently-closed phase II child study is called Av1ation.
AVN-101, a close structural analogue of latrepirdine, is a selective 5-HT6 receptor antagonist which is under development by Avineuro Pharmaceuticals for the treatment of Alzheimer's disease and anxiety disorders. As of November 2013, it is in phase II clinical trials for these indications.
Merotocin (INN) (developmental code name FE-202767), also known as carba-1-(4-FBzlGly7)dOT, is a peptidic agonist of the oxytocin receptor that was derived from oxytocin. It is under development by Ferring Pharmaceuticals for the treatment of preterm mothers with lactation failure requiring lactation support, and is in phase II clinical trials for this indication. Merotocin is potent (EC50 < 0.1 nM) and highly selective (>1000-fold over the related vasopressin receptors).
TS-121 (THY1773) is an orally active, selective vasopressin V1B receptor antagonist which is under development by Taisho Pharmaceutical for the adjunctive treatment of major depressive disorder. As of May 2017, it is in phase II clinical trials for this indication.
ABT-436 is an orally active, highly selective vasopressin V1B receptor antagonist which was under development by Abbott Laboratories and AbbVie for the treatment of major depressive disorder, anxiety disorders, and alcoholism but was discontinued. It reached phase II clinical trials prior to the discontinuation of its development.
JNJ-61393215 is an orexin antagonist medication which is under development for the treatment of depression and anxiety disorders. It is an orally active compound and acts as a selective antagonist of the orexin OX1 receptor (1-SORA). Preliminary clinical findings suggest that JNJ-61393215 may have anti-panic effects in humans. As of November 2021, JNJ-61393215 is in phase 2 clinical trials for the treatment of major depressive disorder and is in the preclinical stage of development for treatment of panic disorder, while no further development has been reported for treatment of other anxiety disorders. The drug was originated and developed by Janssen Pharmaceuticals.
