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Other names | VU-0530244 |
Drug class | Selective peripherally restricted serotonin 5-HT2B receptor antagonist |
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Chemical and physical data | |
Formula | C22H20FN5O |
Molar mass | 389.434 g·mol−1 |
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VU0530244 is a potent, selective, and putatively peripherally restricted serotonin 5-HT2B receptor antagonist which was first described in 2023. [1] [2] [3] Another similar drug, VU0631019, was also described alongside VU0530244. [3] They were identified via high-throughput screening (HTS). [3]
The affinity (IC50 ) of VU0530244 for the serotonin 5-HT2B receptor was found to be 17.3 nM. [3] Its affinity (IC50) values at the serotonin 5-HT2A and 5-HT2C receptors were greater than 10,000 nM (>578-fold less than for the serotonin 5-HT2B receptor). [3] The drug is predicted to be a robust P-glycoprotein substrate and hence is expected to have very limited blood–brain barrier permeability. [3]
Serotonin 5-HT2B receptor antagonists are of interest for potential use in medicine to treat pulmonary arterial hypertension, valvular heart disease, and related cardiopathies. [4] [5] [6] [3] However, reduced serotonin 5-HT2B receptor signaling in the central nervous system has been linked to adverse effects such as impulsivity, suicidality, and sleep disturbances, among others. [7] [3] Such potential side effects can be avoided with the use of peripherally restricted serotonin 5-HT2B receptor antagonists. [3]
In addition, activation of serotonin 5-HT2B receptors is thought to be responsible for development of cardiac fibrosis and valvulopathy as well as pulmonary hypertension with certain serotonergic agents, including direct serotonin 5-HT2B receptor agonists like cabergoline, ergotamine, methysergide, and pergolide, serotonin releasing agents like chlorphentermine and aminorex, and dual serotonin 5-HT2B receptor agonists and serotonin releasing agents like fenfluramine, dexfenfluramine, benfluorex, and MDMA. [8] [9] [10] [11] [12] Serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin as well as entactogens like MDMA are also potent serotonin 5-HT2B receptor agonists, and there have been concerns about chronic administration of these and related agents in medical contexts due to possible development of cardiac and other complications. [13] [14] [15] [16] Selective serotonin 5-HT2B receptor antagonism has been found to fully prevent the cardiotoxicity of dexnorfenfluramine in rodents. [17] [18]
In 2024, the paper that described the discovery of the VU0530244 won the 2023 Rosalind Franklin Society Special Award in Science for contributions to the journal Assay and Drug Development Technologies . [1] [2]
Empathogens or entactogens are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, relatedness, emotional openness—that is, empathy or sympathy—as particularly observed and reported for experiences with 3,4-methylenedioxymethamphetamine (MDMA). This class of drug is distinguished from the classes of hallucinogen or psychedelic, and amphetamine or stimulants. Major members of this class include MDMA, MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, αMT, and αET, MDAI among others. Most entactogens are phenethylamines and amphetamines, although several, such as αMT and αET, are tryptamines. When referring to MDMA and its counterparts, the term MDxx is often used. Entactogens are sometimes incorrectly referred to as hallucinogens or stimulants, although many entactogens such as ecstasy exhibit psychedelic or stimulant properties as well.
Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced dopamine synthesis in the substantia nigra of the brain. Pergolide acts on many of the same receptors as dopamine to increase receptor activity.
Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications. Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.
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Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.
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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).
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