Tag: 5-HT3

What is Quipazine?

Published on by Andrew MarshallLeave a comment

Introduction

Quipazine, also known as 1-(2-quinolinyl)piperazine, is a serotonergic drug of the arylpiperazine family and an analogue of 1-(2-pyridinyl)piperazine which is used in scientific research.

It was first described in the 1960s and was originally intended as an antidepressant but was never developed or marketed for medical use.

Pharmacology

Pharmacodynamics

Quipazine is a serotonin 5-HT3 receptor agonist and to a lesser extent a serotonin 5-HT2A receptor agonist, ligand of the serotonin 5-HT2B and 5-HT2C receptors, and serotonin reuptake inhibitor. Activation of the serotonin 5-HT3 is implicated in inducing nausea and vomiting as well as anxiety, which has limited the potential clinical usefulness of quipazine.

Quipazine produces a head-twitch response and other psychedelic-consistent effects in animal studies including in mice, rats, and monkeys. These effects appear to be mediated by activation of the serotonin 5-HT2A receptor, as they are blocked by serotonin 5-HT2A receptor antagonists like ketanserin. The head twitches induced by quipazine are potentiated by the monoamine oxidase inhibitor (MAOI) pargyline. Based on this, it has been suggested that quipazine may act as a serotonin releasing agent and that it may induce the head twitch response by a dual action of serotonin 5-HT2A receptor agonism and induction of serotonin release.

Quipazine did not produce psychedelic effects in humans up to a dose of 25 mg, which was the highest dose tested due to serotonin 5-HT3 receptor-mediated side effects of nausea and gastrointestinal discomfort. Alexander Shulgin has anecdotally claimed that a fully effective psychedelic dose could be reached by blocking serotonin 5-HT3 receptors using the serotonin 5-HT3 receptor antagonist ondansetron.

Quipazine can produce tachycardia, including positive chronotropic and positive inotropic effects, through activation of the serotonin 5-HT3 receptor.

Although quipazine does not generalise to dextroamphetamine in drug discrimination tests of dextroamphetamine-trained rodents, dextroamphetamine and cathinone have been found to partially generalise to quipazine in assays of quipazine-trained rodents. In relation to this, it has been suggested that quipazine might possess some dopaminergic activity, as the discriminative stimulus properties of amphetamine appear to be mediated by dopamine signalling. Relatedly, quipazine has been said to act as a dopamine receptor agonist in addition to serotonin receptor agonist. Conversely however, the generalisation may be due to serotonergic activities of amphetamine and cathinone. Fenfluramine has been found to fully generalise to quipazine, but levofenfluramine, in contrast to quipazine, did not generalise to dextroamphetamine.

Chemistry

Quipazine is a substituted piperazine and quinoline.

It is structurally related to 6-nitroquipazine and 1-(1-naphthyl)piperazine.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Quipazine >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

An Overview of the 5-HT3 Receptor

Published on by Andrew Marshall10 Comments

Introduction

The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs) and therefore differs structurally and functionally from all other 5-HT receptors (5-hydroxytryptamine, or serotonin receptors) which are G protein-coupled receptors. This ion channel is cation-selective and mediates neuronal depolarisation and excitation within the central and peripheral nervous systems.

As with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to sodium (Na), potassium (K), and calcium (Ca) ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which, in turn, leads to an excitatory response in neurons. The rapidly activating, desensitising, inward current is predominantly carried by sodium and potassium ions. 5-HT3 receptors have a negligible permeability to anions. They are most closely related by homology to the nicotinic acetylcholine receptor.

Brief History

Identification of the 5-HT3 receptor did not take place until 1986, lacking selective pharmacological tools. However, with the discovery that the 5-HT3 receptor plays a prominent role in chemotherapy- and radiotherapy-induced vomiting, and the concomitant development of selective 5-HT3 receptor antagonists to suppress these side effects aroused intense interest from the pharmaceutical industry and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.

Structure

The 5-HT3 receptor differs markedly in structure and mechanism from the other 5-HT receptor subtypes, which are all G-protein-coupled. A functional channel may be composed of five identical 5-HT3A subunits (homopentameric) or a mixture of 5-HT3A and one of the other four 5-HT3B, 5-HT3C, 5-HT3D, or 5-HT3E subunits (heteropentameric). It appears that only the 5-HT3A subunits form functional homopentameric channels. All other subunit subtypes must heteropentamerise with 5-HT3A subunits to form functional channels. Additionally, there has not currently been any pharmacological difference found between the heteromeric 5-HT3AC, 5-HT3AD, 5-HT3AE, and the homomeric 5-HT3A receptor. N-terminal glycosylation of receptor subunits is critical for subunit assembly and plasma membrane trafficking.

The subunits surround a central ion channel in a pseudo-symmetric manner. Each subunit comprises an extracellular N-terminal domain which comprises the orthosteric ligand-binding site; a transmembrane domain consisting of four interconnected alpha helices (M1-M4), with the extracellular M2-M3 loop involved in the gating mechanism; a large cytoplasmic domain between M3 and M4 involved in receptor trafficking and regulation; and a short extracellular C-terminus. Whereas extracellular domain is the site of action of agonists and competitive antagonists, the transmembrane domain contains the central ion pore, receptor gate, and principle selectivity filter that allows ions to cross the cell membrane.

Human and Mouse Genes

The genes encoding human 5-HT3 receptors are located on chromosomes 11 (HTR3A, HTR3B) and 3 (HTR3C, HTR3D, HTR3E), so it appears that they have arisen from gene duplications. The genes HTR3A and HTR3B encode the 5-HT3A and 5-HT3B subunits and HTR3C, HTR3D and HTR3E encode the 5-HT3C, 5-HT3D and 5-HT3E subunits. HTR3C and HTR3E do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased 5-HT efficacies. The pathophysiological role for these additional subunits has yet to be identified.

The human 5-HT3A receptor gene is similar in structure to the mouse gene which has 9 exons and is spread over ~13 kb. Four of its introns are exactly in the same position as the introns in the homologous α7-acetylcholine receptor gene, clearly showing their evolutionary relationship.

  • Expression: The 5-HT3C, 5-HT3D and 5-HT3E genes tend to show peripherally restricted pattern of expression, with high levels in the gut. In human duodenum and stomach, for example, 5-HT3C and 5-HT3E mRNA might be greater than for 5-HT3A and 5-HT3B.
  • Polymorphism: In patients treated with chemotherapeutic drugs, certain polymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the 5-HTR3B receptor subunit could be used as biomarker of antiemetic drug efficacy.

Tissue Distribution

The 5-HT3 receptor is expressed throughout the central and peripheral nervous systems and mediates a variety of physiological functions. On a cellular level, it has been shown that postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons, amygdala, and hippocampus, and in ferret visual cortex. 5-HT3 receptors are also present on presynaptic nerve terminals. There is some evidence for a role in modulation of neurotransmitter release, but evidence is inconclusive.

Effects

When the receptor is activated to open the ion channel by agonists, the following effects are observed:

  • Central nervous system (CNS): nausea and vomiting centre in brain stem, anxiety, as well as anticonvulsant and pro-nociceptive activity.
  • Peripheral nervous system (PNS): neuronal excitation (in autonomic, nociceptive neurons), emesis.

Agonists

Agonists for the receptor include:

  • Cereulide
  • 2-methyl-5-HT
  • Alpha-Methyltryptamine
  • Bufotenin
  • Chlorophenylbiguanide
  • Ethanol
  • Ibogaine
  • Phenylbiguanide
  • Quipazine
  • RS-56812: Potent and selective 5-HT3 partial agonist, 1000x selectivity over other serotonin receptors
  • SR-57227
  • Varenicline
  • YM-31636
  • S 21007(SAR c.f. CGS-12066A)

Antagonists

Antagonists for the receptor (sorted by their respective therapeutic application) include:

  • Antiemetics
    • AS-8112
    • Granisetron
    • Ondansetron
    • Tropisetron
  • Gastroprokinetics
    • Alosetron
    • Batanopride
    • Metoclopramide (high doses)
    • Renzapride
    • Zacopride
    • M1, the major active metabolite of mosapride
  • Antidepressants
  • Antipsychotics
  • Antimalarials
    • Quinine
    • Chloroquine
    • Mefloquine
  • Others
    • 3-Tropanyl indole-3-carboxylate
    • Cannabidiol (CBD)
    • Delta-9-Tetrahydrocannabinol
    • Lamotrigine (epilepsy and bipolar disorder)
    • Memantine (Alzheimer’s disease medication)
    • Menthol
    • Thujone

Positive Allosteric Modulators

These agents are not agonists at the receptor, but increase the affinity or efficacy of the receptors for an agonist:

  • Indole Derivatives
  • 5-chloroindole
  • Small Organic Anaesthetics
  • Ethanol
  • Chloroform
  • Halothane
  • Isoflurane

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/5-HT3_receptor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.