Tag: Azapirone

What is 8-OH-DPAT?

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Introduction

8-OH-DPAT is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonists to be discovered.

Refer to Azapirone.

Originally believed to be selective for the 5-HT1A receptor, 8-OH-DPAT was later found to act as a 5-HT7 receptor agonist and serotonin reuptake inhibitor/releasing agent as well.

In animal studies, 8-OH-DPAT has been shown to possess antidepressant, anxiolytic, serenic, anorectic, antiemetic, hypothermic, hypotensive, bradycardic, hyperventilative, and analgesic effects.

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What is Tandospirone?

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Introduction

Tandospirone, sold under the brand name Sediel, is an anxiolytic and antidepressant medication used in Japan and China, where it is marketed by Dainippon Sumitomo Pharma. It is a member of the azapirone class of drugs and is closely related to other azapirones like buspirone and gepirone.

Tandospirone was introduced for medical use in Japan in 1996 and in China in 2004.

Medical Uses

Anxiety and Depression

Tandospirone is most commonly used as a treatment for anxiety and depressive disorders, such as generalised anxiety disorder and dysthymia respectively. For both indications it usually takes a couple of weeks for therapeutic effects to begin to be seen, although at higher doses more rapid anxiolytic responses have been seen. It has also been used successfully as a treatment for bruxism.

Augmentation for Depression

Tandospirone can be used as an effective augmentation, especially when coupled with fluoxetine or clomipramine.

Other Uses

Tandospirone has been tried successfully as an adjunctive treatment for cognitive symptoms in schizophrenic individuals.

Side Effects

Common adverse effects include:

  • Dizziness
  • Drowsiness
  • Insomnia
  • Headache
  • Gastrointestinal disorders
  • Dry mouth
  • Negative influence on explicit memory function
  • Nausea

Adverse effects with unknown frequency include:

  • Hypotension (low blood pressure)
  • Dysphoria
  • Tachycardia
  • Malaise
  • Psychomotor impairment

It is not believed to be addictive but is known to produce mild withdrawal effects (e.g. anorexia) after abrupt discontinuation.

Pharmacology

Pharmacodynamics

Tandospirone acts as a potent and selective 5-HT1A receptor partial agonist, with a Ki affinity value of 27 ± 5 nM and approximately 55 to 85% intrinsic activity. It has relatively weak affinity for the 5-HT2A (1,300 ± 200), 5-HT2C (2,600 ± 60), α1-adrenergic (1,600 ± 80), α2-adrenergic (1,900 ± 400), D1 (41,000 ± 10,000), and D2 (1,700 ± 300) receptors, and is essentially inactive at the 5-HT1B, 5-HT1D, β-adrenergic, and muscarinic acetylcholine receptors, serotonin transporter, and benzodiazepine allosteric site of the GABAA receptor (all of which are > 100,000). There is evidence of tandospirone having low but significant antagonistic activity at the α2-adrenergic receptor through its active metabolite 1-(2-pyrimidinyl)piperazine (1-PP).

Society and Culture

Name

Tandospirone is also known as metanopirone and by the developmental code name SM-3997. It is marketed in Japan under the brand name Sediel.

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What is Perospirone?

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Introduction

Perospirone (Lullan) is an atypical antipsychotic of the azapirone family. It was introduced in Japan by Dainippon Sumitomo Pharma in 2001 for the treatment of schizophrenia and acute cases of bipolar mania.

Medical Uses

Its primary uses are in the treatment of schizophrenia and bipolar mania.

Schizophrenia

In a clinical trial that compared it to haloperidol in the treatment of schizophrenia it was found to produce significantly superior overall symptom control. In another clinical trial perospirone was compared with mosapramine and produced a similar reduction in total PANSS score, except with respect to the blunted affect part of the PANSS negative score, in which perospirone produced a significantly greater improvement. In an open-label clinical trial comparing aripiprazole with perospirone there was no significant difference between the two treatments discovered in terms of both efficacy and tolerability. In 2009 a clinical trial found that perospirone produced a similar reduction of PANSS score than risperidone and the extrapyramidal side effects was similar in both frequency and severity between groups.

A meta-analysis published in 2013 found that it is statistically significantly less efficacious than other second-generation antipsychotics.

Adverse Effects

Has a higher incidence of extrapyramidal side effects than the other atypical antipsychotics, but still less than that seen with typical antipsychotics. A trend was observed in a clinical trial comparing mosapramine with perospirone that favoured perospirone for producing less prominent extrapyramidal side effects than mosapramine although statistical significant was not reached. It may produce less QT interval (measurement made on an electrocardiogram used to assess some of the electrical properties of the heart) prolongation than zotepine, as in one patient who had previously been on zotepine switching to perospirone corrected their prolonged QT interval. It also tended to produce less severe extrapyramidal side effects than haloperidol in a clinical trial comparing the two (although statistical significance was not reached).

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a felling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

Perospirone binds to the following receptors with very high affinity (as an antagonist unless otherwise specified):

  • 5-HT1A (partial agonist; Ki=2.9 nM)
  • 5-HT2A (inverse agonist; Ki=1.3 nM)
  • D2 (Ki = 0.6 nM)

And the following receptor with high affinity:

  • H1 (inverse agonist)

And the following with moderate affinity:

  • D4
  • α1 adrenoceptor

And with low affinity for the following receptor:

  • D1

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Perospirone >; 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.

What is Umespirone?

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Introduction

Umespirone (KC-9172) is a drug of the azapirone class which possesses anxiolytic and antipsychotic properties.

Outline

It behaves as a 5-HT1A receptor partial agonist (Ki = 15 nM), D2 receptor partial agonist (Ki = 23 nM), and α1-adrenoceptor receptor antagonist (Ki = 14 nM), and also has weak affinity for the sigma receptor (Ki = 558 nM).

Unlike many other anxiolytics and antipsychotics, umespirone produces minimal sedation, cognitive/memory impairment, catalepsy, and extrapyramidal symptoms.

Synthesis

The condensation between ethyl cyanoacetate and acetone gives ethylisopropylidenecyanoacetate 759-58-0. This product is reacted with N-butylcyanoacetamide 39581-21-0 in sodium methoxide solution to give N-butyl-2,4-dicyano-3,3-dimethylglutarimide, CID:10681941. The glutarimide is cyclized with phosphoric acid to yield 3-butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraone, https://pubchem.ncbi.nlm.nih.gov/compound/10825633 CID:10825633.

The reaction between 1-(o-anisyl)piperazine 35386-24-4 and 1,4-dibromobutane 110-52-1 gives the Quat salt CID:15895413.

Convergent synthesis (in the presence of potassium carbonate) affords Umespirone (KC-9172).

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What is Tiospirone?

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Introduction

Tiospirone (BMY-13,859), also sometimes called tiaspirone or tiosperone, is an atypical antipsychotic of the azapirone class.

Outline

It was investigated as a treatment for schizophrenia in the late 1980s and was found to have an effectiveness equivalent to those of typical antipsychotics in clinical trials but without causing extrapyramidal side effects.

However, development was halted and it was not marketed.

Perospirone, another azapirone derivative with antipsychotic properties, was synthesized and assayed several years after tiospirone.

It was found to be both more potent and more selective in comparison and was commercialised instead.

Pharmacology

Pharmacodynamics

Tiospirone acts as a 5-HT1A receptor partial agonist, 5-HT2A, 5-HT2C, and 5-HT7 receptor inverse agonist, and D2, D4, and α1-adrenergic receptor antagonist.

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What is Zalospirone?

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Introduction

Zalospirone (WY-47,846) is a selective 5-HT1A partial agonist of the azapirone chemical class.

It was found to be effective in the treatment of anxiety and depression in clinical trials, but a high proportion of subjects dropped out due to side effects and development was subsequently never completed.

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What is Revospirone?

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Introduction

Revospirone (Bay Vq 7813) is an azapirone drug which was patented as a veterinary tranquiliser but was never marketed.

It acts as a selective 5-HT1A receptor partial agonist.

Similarly to other azapirones such as buspirone, revospirone produces 1-(2-pyrimidinyl)piperazine (1-PP) as an active metabolite.

As a result, it also acts as an α2-adrenergic receptor antagonist to an extent.

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What is Ipsaprione?

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Introduction

Ipsapirone is a selective 5-HT1A receptor partial agonist of the piperazine and azapirone chemical classes.

It has antidepressant and anxiolytic effects.

Ipsapirone was studied in several placebo-controlled trials for depression and continues to be used in research.

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What is Eptapirone?

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Introduction

Eptapirone (F-11,440) is a very potent and highly selective 5-HT1A receptor full agonist of the azapirone family. Its affinity for the 5-HT1A receptor was reported to be 4.8 nM (Ki) (or 8.33 (pKi)), and its intrinsic activity approximately equal to that of serotonin (i.e. 100%).

Eptapirone and related high-efficacy 5-HT1A full and super agonists such as befiradol and F-15,599 were developed under the hypothesis that the maximum exploitable therapeutic benefits of 5-HT1A receptor agonists might not be able to be seen without the drugs employed possessing sufficiently high intrinsic activity at the receptor. As 5-HT1A receptor agonism, based on animal and other research, looked extremely promising for the treatment of depression from a theoretical perspective, this idea was developed as a potential explanation for the relatively modest clinical effectiveness seen with already available 5-HT1A receptor agonists like buspirone and tandospirone, which act merely as weak-to-moderate partial agonists of the receptor.

Animal Studies

In the Porsolt forced swimming test, eptapirone was found to suppress immobility more robustly than buspirone, ipsapirone, flesinoxan, paroxetine, and imipramine, which was suggestive of strong antidepressant-like effects. In this assay, unlike the other drugs screened, buspirone actually increased the immobility time with a single administration, while repeated administration decreased it, an effect that may have been related to buspirone’s relatively weak intrinsic activity (~30%) at the 5-HT1A receptor and/or its preferential activation of 5-HT1A somatodendritic autoreceptors over postsynaptic receptors.

After repeated administration, high dose paroxetine was able to rival the reduction in immobility seen with eptapirone. However, efficacy was seen on the first treatment with eptapirone, which suggested that eptapirone may have the potential for a more rapid onset of antidepressant effectiveness in comparison. Imipramine was unable to match the efficacy of eptapirone or high dose paroxetine, which was probably the result of the fact that higher doses were fatal.

In the conflict procedure, eptapirone produced substantial increases in punished responding without affecting unpunished responding, which was suggestive of marked anxiolytic-like effects. In addition, the efficacy of eptapirone in this assay was more evident than that of buspirone, ipsapirone, and flesinoxan.

Human Studies

Eptapirone has been assayed in humans in preclinical trials at an oral dose of 1.5 mg. In these studies, eptapirone reduced body temperature, prolonged REM sleep, increased cortisol and growth hormone levels, and produced side effects such as dizziness and drowsiness while being overall well tolerated. It peaked rapidly within 30–60 minutes and had an estimated half-life of two hours, with a total duration of approximately three hours.

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What is Enilospirone?

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Introduction

Enilospirone (CERM-3,726) is a selective 5-HT1A receptor agonist of the azapirone class.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Enilospirone >; 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.