Quazepam, sold under brand name Doral among others, is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is used for the treatment of insomnia including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines. Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.
Dihydrexidine (DAR-0100) is a moderately selective full agonist at the dopamine D1 and D5 receptors. It has approximately 10-fold selectivity for D1 and D5 over the D2 receptor. Although dihydrexidine has some affinity for the D2 receptor, it has functionally selective (highly biased) D2 signaling, thereby explaining why it lacks D2 agonist behavioral qualities.
Tripelennamine, sold under the brand name Pyribenzamine by Novartis, is a drug that is used as an antipruritic and first-generation antihistamine. It can be used in the treatment of asthma, hay fever, rhinitis, and urticaria, but is now less common as it has been replaced by newer antihistamines. The drug was patented at CIBA, which merged with Geigy into Ciba-Geigy, and eventually becoming Novartis.
Metopimazine, sold under the brand names Nortrip, Vogalen, and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting. It is marketed in Europe, Canada, and South America. As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis.
The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (HCRTR1, HCRTR2).
Eglumetad is a research drug developed by Eli Lilly and Company, which is being investigated for its potential in the treatment of anxiety and drug addiction. It is a glutamate derived compound and its mode of action implies a novel mechanism.
Terguride, sold under the brand name Teluron, is a serotonin receptor antagonist and dopamine receptor agonist of the ergoline family. It is approved for and used as a prolactin inhibitor in the treatment of hyperprolactinemia in Japan. Terguride is taken by mouth.
Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.
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.
Sufugolix (INN, BAN) (developmental code name TAK-013) is a non-peptide, orally-active, selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (IC50 = 0.1 and 0.06 nM for affinity and in vitro inhibition, respectively). It was under development by Takeda for the treatment of endometriosis and uterine leiomyoma and reached phase II clinical trials for both of these indications, but was subsequently discontinued. It seems to have been supplanted by relugolix (TAK-385), which is also under development by Takeda for the treatment of these conditions and has a more favorable drug profile (including reduced cytochrome P450 inhibition and improved in vivo GnRHR antagonistic activity) in comparison.
Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).
Fevipiprant (INN; code name QAW039) is a drug being developed by Novartis which acts as a selective, orally available antagonist of the prostaglandin D2 receptor 2 (DP2 or CRTh2).
Vilaprisan is a synthetic and steroidal selective progesterone receptor modulator (SPRM) which is under development by Bayer HealthCare Pharmaceuticals for the treatment of endometriosis and uterine fibroids. It is a potent and highly selective partial agonist of the progesterone receptor (PR). As of 2017, the drug is in phase II clinical trials for the aforementioned indications.
Esaxerenone (INN) is a nonsteroidal antimineralocorticoid which was discovered by Exelixis and developed by Daiichi Sankyo Company and is approved in Japan for the treatment of hypertension. It acts as a highly selective silent antagonist of the mineralocorticoid receptor (MR), the receptor for aldosterone, with greater than 1,000-fold selectivity for this receptor over other steroid hormone receptors, and 4-fold and 76-fold higher affinity for the MR relative to the existing antimineralocorticoids spironolactone and eplerenone. As of January 2019, esaxerenone is in phase III clinical trials for diabetic nephropathies.
Apararenone (INN) is a nonsteroidal antimineralocorticoid which is under development by Mitsubishi Tanabe Pharma for the treatment of diabetic nephropathies and non-alcoholic steatohepatitis. It was also previously being developed for the treatment of hypertension, but development was discontinued for this indication. Apararenone acts as a highly selective antagonist of the mineralocorticoid receptor, the receptor for aldosterone. As of 2017, it is in phase II clinical trials.
Danavorexton is a selective orexin 2 receptor agonist. It is a small-molecule compound and is administered intravenously. The compound was found to dose-dependently produce wakefulness to a similar degree as modafinil in a phase 1 clinical trial. As of March 2021, danavorexton is under development for the treatment of narcolepsy, idiopathic hypersomnia, and sleep apnea. It is related to another orexin receptor agonist known as TAK-994, the development of which was discontinued for safety reasons in October 2021.
Bromerguride (INN), also known as 2-bromolisuride, is an antidopaminergic and serotonergic agent of the ergoline group which was described as having atypical antipsychotic properties but was never marketed. It was the first antidopaminergic ergoline derivative to be discovered. The pharmacodynamic actions of bromerguride are said to be "reversed" relative to its parent compound lisuride, a dopaminergic agent.
Deudomperidone (developmental code name CIN-102; also known as deuterated domperidone) is a dopamine antagonist medication which is under development in the United States for the treatment of gastroparesis. It acts as a selective dopamine D2 and D3 receptor antagonist and has peripheral selectivity. Deudomperidone is a deuterated form of domperidone, and it is suggested that deudomperidone may have improved efficacy, tolerability, and pharmacokinetics compared to domperidone. As of January 2022, deudomperidone is in phase 2 clinical trials for the treatment of gastroparesis.
Mevidalen (developmental code name LY-3154207) is a dopaminergic drug which is under development for the treatment of Lewy body disease, including those with Parkinson's disease. It acts as a selective positive allosteric modulator (PAM) of the dopamine D1 receptor. The drug is orally active and crosses the blood–brain barrier. It is a tetrahydroisoquinoline and is a close analogue of DETQ, another D1 receptor PAM. Mevidalen has been found to have wakefulness-promoting effects in sleep-deprived humans. Side effects of mevidalen have been reported to include increased heart rate and blood pressure, insomnia, dizziness, nausea, vomiting, anxiety, nervousness, fatigue, headaches, palpitations, and contact dermatitis, as well as falls in those with dementia. As of March 2022, mevidalen is in phase 2 clinical trials for the treatment of Lewy body disease. Besides for movement disorders and dementia, D1 receptor PAMs like mevidalen might have value in the treatment of certain neuropsychiatric disorders, such as depression, excessive somnolence, and attention deficit hyperactivity disorder.
Threohydrobupropion is a substituted amphetamine derivative—specifically a β-hydroxyamphetamine—and a major active metabolite of the antidepressant drug bupropion (Wellbutrin). Bupropion is a norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator, with its metabolites contributing substantially to its activities. Threohydrobupropion exists as two isomers, (1R,2R)-threohydrobupropion and (1S,2S)-threohydrobupropion. Other metabolites of bupropion include hydroxybupropion and erythrohydrobupropion.
