Azapirones are a class of

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

s used as

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

s, and

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

s. They are commonly used as add-ons to other

s, such as

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

s (SSRIs).

List of azapirones

The azapirones include the following agents: ; Anxiolytics *

Alnespirone Alnespirone (S-20,499) is a selective 5-HT1A receptor full agonist of the azapirone chemical class. It has antidepressant and anxiolytic effects. See also * 8-OH-DPAT * Azapirone Azapirones are a class of drugs used as anxiolytics, anti ...

(S-20,499) *

Binospirone Binospirone (MDL-73,005-EF) is a drug which acts as a partial agonist at 5-HT1A somatodendritic autoreceptors but as an antagonist at postsynaptic 5-HT1A receptors. It has anxiolytic effects. See also * Azapirone Azapirones are a class o ...

(MDL-73,005) * BMY-7,378 (CAS number: ) *

Buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

(Buspar) *

Enilospirone Enilospirone (CERM-3,726) is a selective 5-HT1A receptor agonist of the azapirone class. See also * Azapirone Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as Augmentati ...

(CERM-3,726) * Eptapirone (F-11,440) *

Gepirone Gepirone, sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder. It is taken orally. Side effects of gepirone include dizziness, nausea, insomnia, abdominal pain, and dyspepsia (indigestion). Ge ...

(Exxua) *

Ipsapirone 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 continue ...

(TVX-Q-7,821) * MJ-7378 (CAS number: ) *

Revospirone Revospirone (Bay Vq 7813) is an azapirone drug which was patented as a veterinary medicine, veterinary minor tranquilizers, tranquilizer but was never marketed. It acts as a binding selectivity, selective 5-HT1A receptor, 5-HT1A receptor partial ...

(BAY-VQ-7,813) *

Tandospirone 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 ot ...

(Sediel) *

Zalospirone 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 sid ...

(WY-47,846) ; Antipsychotics *

Perospirone 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 ...

(Lullan) *

Tiospirone Tiospirone (BMY-13,859), also sometimes called tiaspirone or tiosperone, is an atypical antipsychotic of the azapirone class. It was investigated as a treatment for schizophrenia in the late 1980s and was found to have an effectiveness equivalent ...

(BMY-13,859) *

Umespirone Umespirone (KC-9172) is a drug of the azapirone class which possesses anxiolytic and antipsychotic properties. It behaves as a 5-HT1A receptor partial agonist (Ki = 15 nM), D2 receptor partial agonist (Ki = 23 nM), and α1-adrenocep ...

(KC-9,172) ; others *SNAP-8719 (CAS number: )
CID:14086451

Medical uses

Azapirones have shown benefit in general anxiety and augmenting SSRIs in social anxiety and depression. Evidence is not clear for

panic disorder Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...

and

functional gastrointestinal disorder Functional gastrointestinal disorders (FGID), also known as disorders of gut–brain interaction, include a number of separate idiopathic disorders which affect different parts of the human gastrointestinal tract, gastrointestinal tract and involv ...

has also been used to augment antipsychotics in

Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...

as it improves

cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

and

negative symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

s of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

is being investigated for this purpose as well.

Side effects

Side effects of azapirones may include

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

s, restlessness,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, and

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

. Azapirones have more tolerable adverse effects than many other available anxiolytics, such as

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s or SSRIs. Unlike benzodiazepines, azapirones lack

abuse potential Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions ...

and are not

addictive Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

, do not cause cognitive/memory impairment or

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

, and do not appear to induce appreciable tolerance or

physical dependence Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certa ...

. However, azapirones are considered less effective with slow onset in controlling symptoms.

Chemistry

was originally classified as an

azaspirodecanedione Azaspirodecanedione is a chemical compound with the formula C9H13NO2. It is a component of the chemical structures of several of the azapirones. Concrete List #Alnespirone #Binospirone # BMY-7,378 #Buspirone #Gepirone (Dimethyl variation) # Mdl-72 ...

, shortened to azapirone or azaspirone due to the fact that its

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

contained this

moiety Moiety may refer to: __NOTOC__ Anthropology * Moiety (kinship), either of two groups into which a society is divided ** A division of society in the Iroquois societal structure in North America ** An Australian Aboriginal kinship group ** Native Ha ...

, 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

pyrimidinylpiperazine 1-(2-Pyrimidinyl)piperazine (1-PP, 1-PmP) is a chemical compound and piperazine chemical derivative, derivative. It is known to act as an receptor antagonist, antagonist of the α2-adrenergic, α2-adrenergic receptor (Ki = 7.3–40 nM) and ...

s, though again this does not apply to them all. Drugs classed as azapirones can be identified by their -''spirone'' or -''pirone'' suffix.

Pharmacology

Pharmacodynamics

On a

pharmacological Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...

level, azapirones varyingly possess activity at the following

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

s: * 5-HT_1A receptor (as

partial Partial may refer to: Mathematics *Partial derivative, derivative with respect to one of several variables of a function, with the other variables held constant ** ∂, a symbol that can denote a partial derivative, sometimes pronounced "partial d ...

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

s) * 5-HT_2A receptor (as

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

s) * D₂ receptor (as

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.α₁-adrenergic receptor (as antagonists) * α₂-adrenergic receptor (as antagonists) Actions at D₄, 5-HT_2C, 5-HT₇, and

sigma receptor Sigma receptors (σ-receptors) are protein receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 rec ...

s have also been shown for some azapirones. While some of the listed properties such as 5-HT_2A and D₂ blockade may be useful in certain indications such as in the treatment of

(as with perospirone and tiospirone), all of them except 5-HT_1A agonism are generally undesirable in anxiolytics and only contribute to

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

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 was recently approved after completing

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

for the treatment of

major depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

and

generalized anxiety disorder Generalized anxiety disorder (GAD) is an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning. Individuals with GAD are often overly con ...

. Another example is tandospirone which has been licensed in Japan for the treatment of anxiety and as an augmentation to antidepressants for depression. 5-HT_1A receptor partial agonists have demonstrated efficacy against depression in

rodent studies Rodents have been employed in biomedical experimentation from the 1650s. Rodent studies up to the early 19th century were mainly physiological or toxicological. The first rodent behavioral study was carried out in 1822, a purely observational st ...

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 (IA) and efficacy (Emax) refer 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 ...

at 5-HT_1A 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-HT_1A receptor full agonists such as alnespirone and eptapirone. Indeed, in

preclinical studies In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...

, eptapirone produces robust antidepressant effects which surpass those of even high doses of

imipramine Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth. Common s ...

and

paroxetine Paroxetine ( ), sold under the brand name Paxil among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, obsessive-compulsive disorder, o ...

Comparison of binding profiles

Pharmacokinetics

Azapirones are poorly but nonetheless appreciably absorbed and have a rapid

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 meth ...

, but have only very short

half-live Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * '' Half Life: A Parable for t ...

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. Although never commercially produced, Bristol-Myers Squibb applied for a patent on October 28, 1993, and received the patent on July 11, 1995, for an extended release formulation of buspirone. An

extended release Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a spe ...

formulation of gepirone is currently under development and if approved, should help to improve this issue.

Metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of azapirones occurs in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and they are

excreted Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific ...

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

and

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

. A common

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

of several azapirones including

buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

gepirone Gepirone, sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder. It is taken orally. Side effects of gepirone include dizziness, nausea, insomnia, abdominal pain, and dyspepsia (indigestion). Ge ...

ipsapirone 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 continue ...

revospirone Revospirone (Bay Vq 7813) is an azapirone drug which was patented as a veterinary medicine, veterinary minor tranquilizers, tranquilizer but was never marketed. It acts as a binding selectivity, selective 5-HT1A receptor, 5-HT1A receptor partial ...

, and

tandospirone 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 ot ...

1-(2-pyrimidinyl)piperazine 1-(2-Pyrimidinyl)piperazine (1-PP, 1-PmP) is a chemical compound and piperazine derivative. It is known to act as an antagonist of the α2-adrenergic receptor (Ki = 7.3–40 nM) and, to a much lesser extent, as a partial agonist of the 5 ...

(1-PP). 1-PP possesses 5-HT_1A partial agonist and α₂-adrenergic antagonist actions and likely contributes overall mostly to side effects.

References

{{Chemical classes of psychoactive drugs