Azaspirodecanedione
Encyclopedia
Azapirones are a class of drug
s used as anxiolytic
s and antipsychotic
s. They are commonly employed as augmentation
s to antidepressant
s like the selective serotonin reuptake inhibitor
s (SSRIs) as well.
Tandospirone has also been used to augment antipsychotics in Japan
as it improves cognitive and negative symptoms of schizophrenia
. Buspirone is being investigated for this purpose as well.
, shortened to azapirone or azaspirone due to the fact that its chemical structure
contained this moiety
, and other drugs with similar structures were labeled as such as well. However, despite all being called azapirones, not all of them actually contain the azapirodecanedione component, and most in fact do not or contain a variation of it. Additionally, many azapirones are also pyrimidinylpiperazines, though again this does not apply to them all.
Drugs classed as azapirones can be identified by their -spiro or -piro suffix.
s:
Actions at D4, 5-HT2C
, 5-HT7
, and sigma receptor
s have also been shown for some azapirones.
While some of the listed properties such as 5-HT2A and D2 blockade may be useful in certain indications such as in the treatment of schizophrenia
(as with perospirone and tiospirone), all of them except 5-HT1A agonism are generally undesirable in anxiolytics and only contribute to side effect
s. As a result, further development has commenced to bring more selective
of anxiolytic agents to the market. An example of this initiative is gepirone, which is currently in clinical trial
s in the United States
for the treatment of major depression and generalized anxiety disorder. Another example is tandospirone which has been licensed in Japan for the treatment of anxiety and as an augmentation to antidepressants for depression.
5-HT1A receptor partial agonists have demonstrated efficacy against depression in rodent studies and human clinical trials. Unfortunately, however, their efficacy is limited and they are only relatively mild antidepressants. Instead of being used as monotherapy treatments, they are more commonly employed as augmentations to serotonergic antidepressants like the SSRIs. It has been proposed that high intrinsic activity
at 5-HT1A postsynaptic receptors is necessary for maximal therapeutic benefits to come to prominence, and as a result, investigation has commenced in azapirones which act as 5-HT1A receptor full agonists such as alnespirone and eptapirone. Indeed, in preclinical studies
, eptapirone produces robust antidepressant effects which surpass those of even high doses of imipramine
and paroxetine
.
and have a rapid onset of action
, but have only very short half-live
s ranging from 1–3 hours. As a result, they must be administered 2-3 times a day. The only exception to this rule is umespirone, which has a very long duration with a single dose lasting as long as 23 hours. Unfortunately, umespirone has not been commercialized. An extended release formulation of gepirone is currently under development and if approved, should help to improve this issue.
Metabolism
of azapirones occurs in the liver
and they are excreted
in urine
and feces
. A common metabolite
of several azapirones including buspirone
, gepirone
, ipsapirone
, revospirone
, and tandospirone
is 1-(2-pyrimidinyl)piperazine
(1-PP). 1-PP possesses 5-HT1A partial agonist and α2-adrenergic antagonist actions and likely contributes overall mostly to side effects.
, headache
s, restlessness, nausea
, and diarrhea
.
Azapirones have more tolerable adverse effects than many other available anxiolytics like the benzodiazepine
s. Unlike benzodiazepines, azapirones lack abuse potential and are not addictive
, do not cause cognitive/memory impairment
or sedation
, and do not appear to induce appreciable tolerance or physical dependence
. However, azapirones are considered less effective in controlling symptoms in comparison and also require several weeks for their therapeutic benefits to come to prominence.
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s used as anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
s and antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s. They are commonly employed as augmentation
Augmentation (psychiatry)
Augmentation is the combination of two or more drugs to achieve better treatment results....
s to antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s like the selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s (SSRIs) as well.
List of azapirones
The azapirones include the following agents:Tandospirone has also been used to augment antipsychotics in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
as it improves cognitive and negative symptoms of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. Buspirone is being investigated for this purpose as well.
Chemistry
Buspirone was originally classified as an azaspirodecanedioneAzaspirodecanedione
Azapirones are a class of drugs used as anxiolytics and antipsychotics. They are commonly employed as augmentations to antidepressants like the selective serotonin reuptake inhibitors as well.- List of azapirones :...
, shortened to azapirone or azaspirone due to the fact that its chemical structure
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
contained this moiety
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
, and other drugs with similar structures were labeled as such as well. However, despite all being called azapirones, not all of them actually contain the azapirodecanedione component, and most in fact do not or contain a variation of it. Additionally, many azapirones are also pyrimidinylpiperazines, though again this does not apply to them all.
Drugs classed as azapirones can be identified by their -spiro or -piro suffix.
Pharmacodynamics
On a pharmacological level, azapirones varyingly possess activity at the following receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s:
- 5-HT1A receptor5-HT1A receptorThe 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
(as partialPartial agonistPartial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
or full agonists) - 5-HT2A receptor5-HT2A receptorThe mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
(as inverse agonistInverse agonistIn the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
s) - D2 receptor (as antagonistReceptor antagonistA receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
s or partial agonists) - α1-adrenergic receptor (as antagonists)
- α2-adrenergic receptor (as antagonists)
Actions at D4, 5-HT2C
5-HT2C receptor
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
, 5-HT7
5-HT7 receptor
The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin The 5-HT7 receptor is coupled to Gs and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various...
, and sigma receptor
Sigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
s have also been shown for some azapirones.
While some of the listed properties such as 5-HT2A and D2 blockade may be useful in certain indications such as in the treatment of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
(as with perospirone and tiospirone), all of them except 5-HT1A agonism are generally undesirable in anxiolytics and only contribute to side effect
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
s. As a result, further development has commenced to bring more selective
Binding selectivity
Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...
of anxiolytic agents to the market. An example of this initiative is gepirone, which is currently in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
for the treatment of major depression and generalized anxiety disorder. Another example is tandospirone which has been licensed in Japan for the treatment of anxiety and as an augmentation to antidepressants for depression.
5-HT1A receptor partial agonists have demonstrated efficacy against depression in rodent studies and human clinical trials. Unfortunately, however, their efficacy is limited and they are only relatively mild antidepressants. Instead of being used as monotherapy treatments, they are more commonly employed as augmentations to serotonergic antidepressants like the SSRIs. It has been proposed that high intrinsic activity
Intrinsic activity
Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the...
at 5-HT1A postsynaptic receptors is necessary for maximal therapeutic benefits to come to prominence, and as a result, investigation has commenced in azapirones which act as 5-HT1A receptor full agonists such as alnespirone and eptapirone. Indeed, in preclinical studies
Pre-clinical development
In drug development, pre-clinical development is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and drug safety data is collected....
, eptapirone produces robust antidepressant effects which surpass those of even high doses of imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
and paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
.
Pharmacokinetics
Azapirones are poorly but nonetheless appreciably absorbedAbsorption (Pharmacokinetics)
In pharmacology , absorption is the movement of a drug into the bloodstream.Absorption involves several phases...
and have a rapid onset of action
Onset of action
Onset of action is the duration of time it takes for a drug's effects to come to prominence upon administration. With oral administration, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other methods of ingestion such as smoking or injection can...
, but have only very short half-live
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
s ranging from 1–3 hours. As a result, they must be administered 2-3 times a day. The only exception to this rule is umespirone, which has a very long duration with a single dose lasting as long as 23 hours. Unfortunately, umespirone has not been commercialized. An extended release formulation of gepirone is currently under development and if approved, should help to improve this issue.
Metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of azapirones occurs in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and they are excreted
Excretion
Excretion is the process by which waste products of metabolism and other non-useful materials are eliminated from an organism. This is primarily carried out by the lungs, kidneys and skin. This is in contrast with secretion, where the substance may have specific tasks after leaving the cell...
in urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
and feces
Feces
Feces, faeces, or fæces is a waste product from an animal's digestive tract expelled through the anus or cloaca during defecation.-Etymology:...
. A common metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of several azapirones including buspirone
Buspirone
Buspirone is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder Bristol-Myers Squibb gained FDA approval of buspirone in 1986 for treatment of GAD...
, gepirone
Gepirone
Gepirone is a psychoactive drug and research chemical of the piperazine and azapirone chemical classes. It is currently under clinical development in an extended release form as an anxiolytic and antidepressant agent...
, ipsapirone
Ipsapirone
Ipsapirone is a selective 5-HT1A receptor partial agonist of the piperazine and azapirone chemical classes. It has antidepressant and anxiolytic effects.- References :...
, revospirone
Revospirone
Revospirone is a selective 5-HT1A receptor partial agonist of the azapirone class. As with buspirone, gepirone, ipsapirone, and tandospirone, 1-PP is an active metabolite of revospirone; hence, it also has some α2-adrenergic receptor antagonist properties.- References :...
, and tandospirone
Tandospirone
Tandospirone , also known as metanopirone, is an anxiolytic and antidepressant used in China and Japan, where it is marketed by Dainippon Sumitomo Pharma...
is 1-(2-pyrimidinyl)piperazine
1-(2-Pyrimidinyl)piperazine
1-piperazine is a chemical compound and piperazine derivative. It is known to act as an α2-adrenergic receptor antagonist, and as a 5-HT1A receptor partial agonist to a much lesser extent...
(1-PP). 1-PP possesses 5-HT1A partial agonist and α2-adrenergic antagonist actions and likely contributes overall mostly to side effects.
Side effects
Side effects of azapirones may include dizzinessDizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, restlessness, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
.
Azapirones have more tolerable adverse effects than many other available anxiolytics like the benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s. Unlike benzodiazepines, azapirones lack abuse potential and are not addictive
Substance use disorder
Substance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder"....
, do not cause cognitive/memory impairment
Cognitive deficit
Cognitive deficit, also known as cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to cognitive performance...
or sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, and do not appear to induce appreciable tolerance or physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
. However, azapirones are considered less effective in controlling symptoms in comparison and also require several weeks for their therapeutic benefits to come to prominence.