Bexicaserin

Last updated

Bexicaserin
Bexicaserin.svg
Clinical data
Other namesLP352; LP-352; AN352; AN-352
Routes of
administration
Oral [1]
Drug class Serotonin 5-HT2C receptor agonist [1] [2]
Pharmacokinetic data
Elimination half-life 5–7 hours [2]
Identifiers
  • (3R)-N-(2,2-difluoroethyl)-3-methyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-5-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C15H19F2N3O
Molar mass 295.334 g·mol−1
3D model (JSmol)
  • C[C@H]1CN2CCNCC3=C2C1=C(C=C3)C(=O)NCC(F)F
  • InChI=1S/C15H19F2N3O/c1-9-8-20-5-4-18-6-10-2-3-11(13(9)14(10)20)15(21)19-7-12(16)17/h2-3,9,12,18H,4-8H2,1H3,(H,19,21)/t9-/m0/s1
  • Key:KGOOOHQKLRUVSF-VIFPVBQESA-N

Bexicaserin (INN Tooltip International Nonproprietary Name; developmental code names LP352 and AN352) is a selective serotonin 5-HT2C receptor agonist which is under development for the treatment of seizures in developmental disabilities such as Dravet syndrome and Lennox-Gastaut syndrome. [1] [3] [2] It is taken by mouth. [2] [1]

The drug is highly selective for the serotonin 5-HT2C receptor, with negligible affinity for the serotonin 5-HT2A and 5-HT2B receptors. [2] Because it does not activate the serotonin 5-HT2B receptor, bexicaserin is not expected to pose a risk of cardiac valvulopathy, unlike the existing agent fenfluramine. [2]

As of October 2024, bexicaserin is in phase 3 clinical trials for treatment of developmental disabilities. [1] [3] It is being developed by Longboard Pharmaceuticals. [1] [3]

The activation of 5HT2c receptors has been shown to reduce epileptic seizure activity by inhibiting CaV3 calcium channels which mediate the T-type calcium current. [4] CaV3 calcium channels facilitate high frequency burst firing in princible neurons of the subiculum. This firing pattern is upregulated following status epilepticus, with these hyperactive neurons often serving as the initiation point for seizures. [5] [6] [7]

See also

Related Research Articles

The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.

<span class="mw-page-title-main">Dendritic spine</span> Small protrusion on a dendrite that receives input from a single axon

A dendritic spine is a small membrane protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head, and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons. It has also been suggested that changes in the activity of neurons have a positive effect on spine morphology.

<span class="mw-page-title-main">AMPA receptor</span> Transmembrane protein family

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic transmembrane receptor for glutamate (iGluR) and predominantly Na+ ion channel that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core (GluA2 LBD) was the first glutamate receptor ion channel domain to be crystallized.

In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.

<span class="mw-page-title-main">5-HT receptor</span> Class of transmembrane proteins

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

<span class="mw-page-title-main">Kainate receptor</span> Class of ionotropic glutamate receptors

Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the algae Digenea simplex. They have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than AMPA and NMDA receptors, the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.

<span class="mw-page-title-main">Neuromodulation</span> Regulation of neurons by neurotransmitters

Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include altering intrinsic firing activity, increasing or decreasing voltage-dependent currents, altering synaptic efficacy, increasing bursting activity and reconfiguring synaptic connectivity.

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5-HT<sub>2B</sub> receptor Mammalian protein found in Homo sapiens

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.

<span class="mw-page-title-main">Chloride potassium symporter 5</span> Protein-coding gene in the species Homo sapiens

Potassium-chloride transporter member 5 is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentrations. It is a critical mediator of synaptic inhibition, cellular protection against excitotoxicity and may also act as a modulator of neuroplasticity. Potassium-chloride transporter member 5 is also known by the names: KCC2 for its ionic substrates, and SLC12A5 for its genetic origin from the SLC12A5 gene in humans.

Low-threshold spikes (LTS) refer to membrane depolarizations by the T-type calcium channel. LTS occur at low, negative, membrane depolarizations. They often follow a membrane hyperpolarization, which can be the result of decreased excitability or increased inhibition. LTS result in the neuron reaching the threshold for an action potential. LTS is a large depolarization due to an increase in Ca2+ conductance, so LTS is mediated by calcium (Ca2+) conductance. The spike is typically crowned by a burst of two to seven action potentials, which is known as a low-threshold burst. LTS are voltage dependent and are inactivated if the cell's resting membrane potential is more depolarized than −60mV. LTS are deinactivated, or recover from inactivation, if the cell is hyperpolarized and can be activated by depolarizing inputs, such as excitatory postsynaptic potentials (EPSP). LTS were discovered by Rodolfo Llinás and coworkers in the 1980s.

<span class="mw-page-title-main">Spike-and-wave</span>

Spike-and-wave is a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. A spike-and-wave discharge is a regular, symmetrical, generalized EEG pattern seen particularly during absence epilepsy, also known as ‘petit mal’ epilepsy. The basic mechanisms underlying these patterns are complex and involve part of the cerebral cortex, the thalamocortical network, and intrinsic neuronal mechanisms.

Epileptogenesis is the gradual process by which a typical brain develops epilepsy. Epilepsy is a chronic condition in which seizures occur. These changes to the brain occasionally cause neurons to fire in an abnormal, hypersynchronous manner, known as a seizure.

<span class="mw-page-title-main">Nonsynaptic plasticity</span> Form of neuroplasticity

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The ribbon synapse is a type of neuronal synapse characterized by the presence of an electron-dense structure, the synaptic ribbon, that holds vesicles close to the active zone. It is characterized by a tight vesicle-calcium channel coupling that promotes rapid neurotransmitter release and sustained signal transmission. Ribbon synapses undergo a cycle of exocytosis and endocytosis in response to graded changes of membrane potential. It has been proposed that most ribbon synapses undergo a special type of exocytosis based on coordinated multivesicular release. This interpretation has recently been questioned at the inner hair cell ribbon synapse, where it has been instead proposed that exocytosis is described by uniquantal release shaped by a flickering vesicle fusion pore.

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<span class="mw-page-title-main">Tripartite synapse</span>

Tripartite synapse refers to the functional integration and physical proximity of:

<span class="mw-page-title-main">Glutamate (neurotransmitter)</span> Anion of glutamic acid in its role as a neurotransmitter

In neuroscience, glutamate is the anion of glutamic acid in its role as a neurotransmitter. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

BMB-101 is a serotonin 5-HT2C receptor agonist which is under development for the treatment of absence epilepsy, Pitt-Hopkins syndrome, Dravet syndrome, binge-eating disorder, Lennox-Gastaut syndrome, and opioid-related disorders. It is taken by mouth.

References

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  3. 1 2 3 "Delving into the Latest Updates on Bexicaserin with Synapse". Synapse. 28 October 2024. Retrieved 29 October 2024.
  4. Petersen AV, Jensen CS, Crépel V, Falkerslev M, Perrier JF (2017). "Serotonin Regulates the Firing of Principal Cells of the Subiculum by Inhibiting a T-type Ca2+ Current". Frontiers in Cellular Neuroscience. 11: 60. doi: 10.3389/fncel.2017.00060 . PMC   5339341 . PMID   28326015.
  5. Menendez de la Prida L, Gal B (June 2004). "Synaptic contributions to focal and widespread spatiotemporal dynamics in the isolated rat subiculum in vitro". The Journal of Neuroscience : The Official Journal of the Society for Neuroscience. 24 (24): 5525–36. doi:10.1523/JNEUROSCI.0309-04.2004. PMC   6729319 . PMID   15201325.
  6. Su H, Sochivko D, Becker A, Chen J, Jiang Y, Yaari Y, et al. (May 2002). "Upregulation of a T-type Ca2+ channel causes a long-lasting modification of neuronal firing mode after status epilepticus". The Journal of Neuroscience : The Official Journal of the Society for Neuroscience. 22 (9): 3645–55. doi:10.1523/JNEUROSCI.22-09-03645.2002. PMC   6758371 . PMID   11978840.
  7. Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science. 2002 Nov 15;298(5597):1418-21. doi: 10.1126/science.1076510. PMID: 12434059.