The lead section of this article may need to be rewritten.(August 2023) |
Clinical data | |
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Other names | CVL-865; PF-06372865; PF-6372865 |
Routes of administration | Oral administration |
Drug class | GABAA receptor positive allosteric modulator |
Pharmacokinetic data | |
Metabolism | CYP3A4 [1] |
Elimination half-life | 11 hours [1] |
Identifiers | |
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CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
ChemSpider | |
UNII | |
ChEMBL | |
Chemical and physical data | |
Formula | C22H21FN4O3S |
Molar mass | 440.49 g·mol−1 |
3D model (JSmol) | |
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Darigabat (developmental code names CVL-865, PF-06372865, PF-6372865) is a GABAergic medication which is under development for the treatment of photosensitive epilepsy, focal onset seizures, panic disorder, and other anxiety disorders. [2] [3] It was also under development for the treatment of generalized anxiety disorder and chronic lower back pain, but development for these indications was discontinued. [2] [3] [4] It is taken via oral administration. [2]
Darigabat acts as a GABAA receptor positive allosteric modulator, also known as a GABAkine. [2] [3] [5] It is specifically a positive allosteric modulator that selectively targets α2, α3, and α5 subunit-containing GABAA receptors, with minimal functional activity at α1 subunit-containing GABAA receptors. [3] [5] A dose of darigabat that achieved more than 80% receptor occupancy showed no somnolence with dose titration, whereas benzodiazepines, which are non-selective GABAA receptor positive allosteric modulators, achieve only 10 to 15% receptor occupancy whilst producing significant or severe somnolence. [3] [5] It is theorized that α1 subunit-containing GABAA receptors preferentially mediate sedation, amnesia, and ataxia, whereas α2 and α3 subunit-containing GABAA receptors mediate anxiolysis. [3] [5] However, this model has also been questioned. [4] α1 subunit-containing GABAA receptors are said to be completely unaffected by darigabat. [6] The elimination half-life of darigabat is 11 hours and it is metabolized mainly by CYP3A4. [1]
In clinical trials conducted thus far, side effects of darigabat have included dizziness, fatigue, headache, mild-to-moderate somnolence, bradyphrenia (slowness of thought), modest memory impairment, mild cognitive impairment, balance impairment, and feeling abnormal. [3] [6] It has been described as well-tolerated. [3] [4]
Darigabat was originated by Pfizer and is under development by Cerevel Therapeutics and Pfizer. [2] As of January 2023, it is in phase 2 clinical trials for epilepsy and seizures, phase 1 trials for panic disorder, and preclinical development for anxiety disorders. [2] [3] Development for back pain was discontinued due to lack of effectiveness in a phase 2 trial, while development for generalized anxiety disorder was discontinued due to business reasons as well as lack of effectiveness in a phase 2 trial. [3] [4] [2]
Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavioral changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available in conventional tablets, sublingual tablets, or oral spray.
The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−).
Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.
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Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is given by injection into a vein.
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Etifoxine, sold under the trade name Stresam among others, is a nonbenzodiazepine anxiolytic agent, primarily indicated for short-term management of adjustment disorder, specifically instances of situational depression accompanied by anxiety, such as stress-induced anxiety. Administration is by mouth. Side effects associated with etifoxine use include slight drowsiness, headache, skin eruptions, and allergic reactions. In rare cases, etifoxine has been linked to severe skin and liver toxicity, as well as menstrual bleeding between periods. Unlike benzodiazepines, etifoxine does not cause sedation or lack of coordination. Etifoxine acts as a GABAA receptor positive allosteric modulator and as a ligand for translocator proteins. Both mechanisms are conjectured to contribute to its anxiolytic properties.
L-838,417 is an anxiolytic drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. The compound was developed by Merck, Sharp and Dohme.
SL651498 is an anxiolytic and anticonvulsant drug used in scientific research, with a chemical structure most closely related to β-carboline derivatives such as abecarnil and gedocarnil. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.
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In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.
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