Decynium-22

Last updated
Decynium-22
Pseudoisocyanine.svg
Names
Preferred IUPAC name
1-Ethyl-2-[(E)-(1-ethylquinolin-2(1H)-ylidene)methyl]quinolin-1-ium iodide
Other names
  • Decynium-22
  • Pseudocyanine iodide
  • Pseudoisocyanine iodide
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.012.324 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 213-556-6
PubChem CID
UNII
  • InChI=1S/C23H23N2.HI/c1-3-24-20(15-13-18-9-5-7-11-22(18)24)17-21-16-14-19-10-6-8-12-23(19)25(21)4-2;/h5-17H,3-4H2,1-2H3;1H/q+1;/p-1
    Key: GMYRVMSXMHEDTL-UHFFFAOYSA-M
  • InChI=1/C23H23N2.HI/c1-3-24-20(15-13-18-9-5-7-11-22(18)24)17-21-16-14-19-10-6-8-12-23(19)25(21)4-2;/h5-17H,3-4H2,1-2H3;1H/q+1;/p-1
    Key: GMYRVMSXMHEDTL-REWHXWOFAU
  • CCN1C(=CC2=[N+](C3=CC=CC=C3C=C2)CC)C=CC4=CC=CC=C41.[I-]
Properties
C23H23IN2
Molar mass 454.355 g·mol−1
AppearanceDark red powder
Melting point 273 °C (523 °F; 546 K)
Solubility 4.54 mg/ml in DMSO
Hazards
NFPA 704 (fire diamond)
NFPA 704.svgHealth 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
1
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Decynium-22 is a cationic derivative of quinoline, and a potent inhibitor of the plasma membrane monoamine transporter (PMAT), as well as all members of the organic cation transporter (OCT) family in both human and rat cells. [1] However, it has little effect on high affinity monoamine transporters such as the dopamine transporter and norepinephrine transporter. [2]

Contents

Transporter inhibition

Decynium has been shown to have a very high affinity to organic cation transporters in a variety of species, including human, [3] [4] rat, [5] and pig. [6] Decynium-22 has been shown to block the uptake of the neurotoxin 1-methyl-4-phenylpyridinium (MPP) via the OCT3 transporter in rat astrocytes. [7]

Fluorescence

Decynium-22 emits a low fluorescence yield (around 0.001), and in its monomeric form is a weakly fluorescent. However, aggregated decynium-22 emits a strong superradiant emission with a maximum near 570–580 nm. [8] [9] 480 nm light falls near a short wavelength peak of the excitation spectrum of these aggregates. Decynium-22 fluorescence caused by aggregation can be observed in astrocytes. [2]

Schizophrenia and depression

Decynium-22 has recently been investigated for its role in increasing extracellular serotonin in the brain in neuropharmacology research. The transportation of the neurotransmitter serotonin is often disrupted in psychiatric disorders characterized by social impairment, such as schizophrenia and depression. Serotonin is primarily taken up by the 5-HT transporter (SERT), although it is also taken up by auxiliary transporters, known as "uptake 2", which include OCT and PMAT.

The most commonly prescribed antidepressant drugs are the selective serotonin reuptake inhibitors (SSRIs), which act by blocking the high affinity SERT. A proposed explanation for the limited efficacy of SSRIs is the presence of the low affinity transporters OCT and PMAT, which limit the ability of SSRIs to increase extracellular serotonin. Decynium-22 blocked serotonin uptake via these auxiliary transporters, and when used in conjunction with SSRIs, decynium-22 enhanced the effects of SSRIs to inhibit serotonin clearance. [10] A similar effect was seen in SERT knock-out mice, which resulted in an improvement of social behavior. [11] When OCT3 was knocked out in mice, however, decynium-22 was ineffectual, indicating that the anti-depressant effects of decynium-22 are dependent upon its blockage of the OCT3. [10]

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">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

<span class="mw-page-title-main">Serotonin transporter</span> Mammalian protein found in humans

The serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein that transports the neurotransmitter serotonin from the synaptic cleft back to the presynaptic neuron, in a process known as serotonin reuptake.

The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses, as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.

<span class="mw-page-title-main">Phenyltropane</span> Class of chemical compounds

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

<span class="mw-page-title-main">Serotonin reuptake inhibitor</span> Class of drug

A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin by blocking the action of the serotonin transporter (SERT). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission. It is a type of monoamine reuptake inhibitor (MRI); other types of MRIs include dopamine reuptake inhibitors and norepinephrine reuptake inhibitors.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">SLC22A2</span> Protein-coding gene

Solute carrier family 22 member 2 is a protein that in humans is encoded by the SLC22A2 gene.

<span class="mw-page-title-main">SLC22A3</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 22 member 3 (SLC22A3) also known as the organic cation transporter 3 (OCT3) or extraneuronal monoamine transporter (EMT) is a protein that in humans is encoded by the SLC22A3 gene.

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

Nisoxetine, originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently has no clinical applications in humans, although it was originally researched as an antidepressant. Nisoxetine is now widely used in scientific research as a standard selective norepinephrine reuptake inhibitor. It has been used to research obesity and energy balance, and exerts some local analgesia effects.

<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.

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

Talsupram is a selective norepinephrine reuptake inhibitor (NRI) which was investigated as an antidepressant in the 1960s and 1970s but was never marketed. Along with talopram, it is structurally related to the selective serotonin reuptake inhibitor (SSRI) citalopram.

<span class="mw-page-title-main">Serotonin–dopamine reuptake inhibitor</span> Class of drug

A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.

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.

The pharmacology of antidepressants is not entirely clear. The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis, which states that depression is due to an imbalance of the monoamine neurotransmitters. It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway. Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid, robust and sustained antidepressant effects. Monoamine precursor depletion also fails to alter mood. To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses. Another hypothesis that has been proposed which would explain the delay is the hypothesis that monoamines don't directly influence mood, but influence emotional perception biases.

Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have application as antidepressants and in the treatment of depression and other psychiatric disorders. SSRIs are therapeutically useful in the treatment of panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), and anorexia. There is also clinical evidence of the value of SSRIs in the treatment of the symptoms of schizophrenia and their ability to prevent cardiovascular diseases.

<span class="mw-page-title-main">SLC22A13</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 22 member 13 is a protein that in humans is encoded by the SLC22A13 gene.

References

  1. ↑ "Decynium-22". University of California, San Francisco. Archived from the original on 17 October 2014. Retrieved 16 Oct 2014.
  2. 1 2 Inyushin M, Kucheryaykh Y, Kucheryavykh L, Sanabria P, Jiménez-Rivera C, Struganova I, et al. (2010). "Membrane potential and pH-dependent accumulation of decynium-22 (1,1′-diethyl-2,2′-cyanine iodide) fluorescence through the low affinity OCT transporters in astrocytes". Bol Asoc Med P R. 102 (3): 5–12. PMC   3721433 . PMID   23875515.
  3. ↑ Russ H, Sonna J, Keppler K, Baunach S, Schömig E (1993). "Cyanine-related compounds: a novel class of potent inhibitors of extraneuronal noradrenaline transport". Naunyn-Schmiedeberg's Arch Pharmacol. 348 (5): 458–65. doi:10.1007/bf00173203. PMID   8114944. S2CID   6093183.
  4. ↑ Hayer-Zillgen M, Brüss M, Bönisch H (2002). "Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3". Br J Pharmacol. 136 (6): 829–36. doi:10.1038/sj.bjp.0704785. PMC   1573414 . PMID   12110607.
  5. ↑ Gründemann D, Gorboulev V, Gambaryan S, Veyhl M, Koepsell H (1994). "Drug excretion mediated by a new prototype of polyspecific transporter". Nature. 372 (6506): 549–552. Bibcode:1994Natur.372..549G. doi:10.1038/372549a0. PMID   7990927. S2CID   659539.
  6. ↑ Gründemann D, Babin-Ebell J, Martel F, Ording N, Schmidt A, Schömig E (1997). "Primary structure and functional expression of the apical organic cation transporter from kidney epithelial LLC-PK1 cells". J Biol Chem. 272 (16): 10408–13. doi: 10.1074/jbc.272.16.10408 . PMID   9099681.
  7. ↑ Inazu M, Takeda H, Matsumiya T (2003). "Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes". J Neurochem. 84 (1): 43–52. doi: 10.1046/j.1471-4159.2003.01566.x . PMID   12485400.
  8. ↑ Stiel H, Daehne S, Teuchner K. J-aggregates of pseudoisocyanine in solution: New data from nonlinear spectroscopy. J Lumines. 1988;39:351–357.
  9. ↑ Struganova IA. Dynamics of formation of 1,1′-diethyl-2,2′-cyanine iodide J-aggregates in solution. J Physical Chem A. 2000;104:9670–9674.
  10. 1 2 Horton RE, Apple DM, Owens WA, Baganz NL, Cano S, Mitchell NC, et al. (2013). "Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression". J Neurosci. 33 (25): 10534–43. doi:10.1523/JNEUROSCI.5687-11.2013. PMC   3685842 . PMID   23785165.
  11. ↑ Loginova LG, Iakovleva MB, Golovina IG, Bogdanova TI (1976). "[Yeast cell wall-dissolving enzymes of the thermotolerant actinomycete Thermoactinomyces vulgaris]". Mikrobiologiia. 45 (2): 291–7. PMID   6860.
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