LY-2365109

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LY-2365109
LY-2365109.svg
Names
IUPAC name
2-[2-[4-(1,3-Benzodioxol-5-yl)-2-tert-butylphenoxy]ethyl-methylamino]acetic acid
Identifiers
3D model (JSmol)
PubChem CID
  • CC(C)(C)C1=C(C=CC(=C1)C2=CC3=C(C=C2)OCO3)OCCN(C)CC(=O)O
Properties
C22H27NO5
Molar mass 385.460 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

LY-2365109 is a glycine reuptake inhibitor. It is able to inhibit the type 1 glycine transporter. [1] This inhibition increases extracellular levels of glycine. LY-2365109 has been shown to increase the seizure threshold in mice, meaning that this drug has potential as an anticonvulsant. [2]

Related Research Articles

<span class="mw-page-title-main">Reuptake</span> Reabsorption of a neurotransmitter by a neurotransmitter transporter

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.

<span class="mw-page-title-main">Sarcosine</span> Chemical compound

Sarcosine, also known as N-methylglycine, or monomethylglycine, is a amino acid with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2, which can be obtained as a white, water-soluble powder. Like some amino acids, sarcosine converts to a cation at low pH and an anion at high pH, with the respective formulas CH3N+(H)2CH2CO2H and CH3N(H)CH2CO2. Sarcosine is a close relative of glycine, with a secondary amine in place of the primary amine.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

The Na–K–Cl cotransporter (NKCC) is a transport protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes. Two isoforms of the NKCC1/Slc12a2 gene result from keeping or skipping exon 21 in the final gene product.

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

<span class="mw-page-title-main">Sodium- and chloride-dependent glycine transporter 2</span> Protein-coding gene in the species Homo sapiens

Sodium- and chloride-dependent glycine transporter 2, also known as glycine transporter 2 (GlyT2), is a protein that in humans is encoded by the SLC6A5 gene.

<span class="mw-page-title-main">Sodium- and chloride-dependent glycine transporter 1</span> Protein-coding gene in the species Homo sapiens

Sodium- and chloride-dependent glycine transporter 1, also known as glycine transporter 1, is a protein that in humans is encoded by the SLC6A9 gene which is promising therapeutic target for treatment of diabetes and obesity.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<span class="mw-page-title-main">Plasma membrane monoamine transporter</span> Protein-coding gene in the species Homo sapiens

The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene. It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). It was discovered in 2004 and has been identified as a potential alternate target for treating various conditions.

Endocannabinoid reuptake inhibitors (eCBRIs), also called cannabinoid reuptake inhibitors (CBRIs), are drugs which limit the reabsorption of endocannabinoid neurotransmitters by the releasing neuron.

<span class="mw-page-title-main">ORG-25935</span> Synthetic drug

ORG-25935, also known as SCH-900435 is a synthetic drug developed by Organon International, which acts as a selective inhibitor of the glycine transporter GlyT-1. In animal tests it reduces alcohol consumption and has analgesic and anticonvulsant effects, but it has mainly been studied for its antipsychotic properties, and in human trials it was shown to effectively counteract the effects of the dissociative drug ketamine.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

<i>N</i>-Arachidonylglycine Chemical compound

N-Arachidonylglycine (NAGly) is a carboxylic metabolite of the endocannabinoid anandamide (AEA). Since it was first synthesized in 1996, NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids. Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor. NaGly is an endogenous inhibitor of fatty acid amide hydrolase (FAAH) and thereby increases the ethanolamide endocannabinoids AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels. NaGly is found throughout the body and research on its explicit functions is ongoing.

<span class="mw-page-title-main">7-Chlorokynurenic acid</span> Chemical compound

7-Chlorokynurenic acid (7-CKA) is a tool compound that acts as a potent and selective competitive antagonist of the glycine site of the NMDA receptor. It produces ketamine-like rapid antidepressant effects in animal models of depression. However, 7-CKA is unable to cross the blood-brain-barrier, and for this reason, is unsuitable for clinical use. As a result, a centrally-penetrant prodrug of 7-CKA, 4-chlorokynurenine (AV-101), has been developed for use in humans, and is being studied in clinical trials as a potential treatment for major depressive disorder, and anti-nociception. In addition to antagonizing the NMDA receptor, 7-CKA also acts as a potent inhibitor of the reuptake of glutamate into synaptic vesicles, an action that it mediates via competitive blockade of vesicular glutamate transporters.

An excitatory amino acid reuptake inhibitor (EAARI) is a type of drug which inhibits the reuptake of the excitatory neurotransmitters glutamate and aspartate by blocking one or more of the excitatory amino acid transporters (EAATs).

<span class="mw-page-title-main">Pesampator</span> Chemical compound

Pesampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Pfizer for the treatment of cognitive symptoms in schizophrenia. In March 2018, the development of the drug was transferred over from Pfizer to Biogen. It was also under development for the treatment of age-related sensorineural hearing loss, but development for this indication was terminated due to insufficient effectiveness. In July 2022, Biogen discontinued the development of pesampator for cognitive symptoms in schizophrenia due to ineffectiveness.

<span class="mw-page-title-main">Iclepertin</span> Chemical compound

Iclepertin is an investigational nootropic to enhance the cognition and functional capacity in schizophrenia developed by Boehringer Ingelheim. As of May 2020, it is in phase III of clinical trial under the code name CONNEX-3. BI 425809 is an inhibitor of glycine transporter 1 (Gly-T1) that in phase II improved cognition after 12 weeks in patients with schizophrenia. Doses of 10 mg and 25 mg showed the largest separation from placebo. If these encouraging results are confirmed in phase 3 trials, BI 425809 could provide an effective treatment for cognitive impairment associated with schizophrenia. Schizophrenia is characterized by abnormalities in glutamatergic pathways related to NMDA receptor hypofunction. Inhibition of GlyT1 on the presynaptic membrane or astrocytes is hypothesized to increase glycine levels within the synapse. The NMDA receptor function may be enhanced by increasing levels of its co-agonist, glycine, within the synaptic cleft, which may lead to improvements in cognitive function.

<span class="mw-page-title-main">LY-393558</span> Chemical compound

LY-393558 is a potent serotonin reuptake inhibitor and antagonist of the 5-HT1B, 5-HT1D, and 5-HT2A receptors. LY-393558 was also found to reduce serotonin-induced vasoconstriction, indicating that it may have therapeutic potential for the treatment of pulmonary hypertension.

<span class="mw-page-title-main">ALX-1393</span> Glycine reuptake inhibitor

ALX-1393 is a glycine reuptake inhibitor.

<span class="mw-page-title-main">ORG-24598</span> Selective inhibitor of Glycine transporter 1

ORG-24598 is a selective inhibitor of the type 1 glycine transporter.

References

  1. Zhang, Jichun; Wu, Jin; Toyohara, Jun; Fujita, Yuko; Chen, Hongxian; Hashimoto, Kenji (2011). "Pharmacological characterization of [³H]CHIBA-3007 binding to glycine transporter 1 in the rat brain". PLOS ONE. 6 (6): e21322. Bibcode:2011PLoSO...621322Z. doi: 10.1371/journal.pone.0021322 . ISSN   1932-6203. PMC   3121759 . PMID   21731704.
  2. Shen, Hai-Ying; van Vliet, Erwin A.; Bright, Kerry-Ann; Hanthorn, Marissa; Lytle, Nikki K.; Gorter, Jan; Aronica, Eleonora; Boison, Detlev (December 2015). "Glycine transporter 1 is a target for the treatment of epilepsy". Neuropharmacology. 99: 554–565. doi:10.1016/j.neuropharm.2015.08.031. ISSN   1873-7064. PMC   4655139 . PMID   26302655.