Eptapirone
Encyclopedia
Eptapirone is a very potent
and highly selective
5-HT1A receptor
full agonist of the azapirone class. Its affinity for the 5-HT1A receptor is 4.8 nM (Ki) or 8.33 (pKi), and its intrinsic activity
is 100% or equal to that of serotonin
.
Eptapirone and its relatives such as F-13,640 and F-15,599
were developed under the notion that high receptor-activating efficacy is required for the maximal therapeutic benefits of 5-HT1A receptor agonists to be realized, underlying the poor clinical effectiveness of currently marketed agents like buspirone
and tandospirone
which act as mere weak-moderate partial agonist
s.
, flesinoxan
, paroxetine
, and imipramine
, indicating that it possesses powerful antidepressant
effects which may be superior to those of currently available pharmaceuticals. In this test, unlike the other agents screened, buspirone actually increases immobility time with a single administration, while repeated administration decreases it, likely as a result of buspirone's very poor intrinsic activity (~30%) in activating the 5-HT1A receptor.
While high dose paroxetine is able to rival the reduction in immobility induced by eptapirone, it is only able to do so after repeated administration (in contrast to eptapirone which requires only a single dose), suggesting that eptapirone has a more rapid onset of action
than other antidepressants as well. Imipramine was unable to match eptapirone or high dose paroxetine's efficacy as greater doses were fatal.
In the conflict procedure
, eptapirone produces substantial increases in punished responding without affecting unpunished responding, demonstrating marked anxiolytic
effects. Furthermore, these effects are more evident than those afforded by buspirone, ipsapirone, and flesinoxan.
s in preclinical trials at an oral
dose
of 1.5 mg. In these studies, eptapirone reduces body temperature, suppresses REM sleep, increases cortisol
and growth hormone
levels, and produces side effect
s including dizziness
and drowsiness while being overall well-tolerated. It peaks rapidly within 30–60 minutes and has an estimated half-life
of two hours, with a total duration of approximately three hours.
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
and highly 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...
5-HT1A receptor
5-HT1A receptor
The 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...
full agonist of the azapirone class. Its affinity for the 5-HT1A receptor is 4.8 nM (Ki) or 8.33 (pKi), and its 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...
is 100% or equal to that of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
.
Eptapirone and its relatives such as F-13,640 and F-15,599
F-15,599
F-15,599 is a very potent and highly selective 5-HT1A receptor full agonist. It displays functional selectivity by strongly activating 5-HT1A receptors in the prefrontal cortex while having little effect on autoreceptors in the raphe nucleus...
were developed under the notion that high receptor-activating efficacy is required for the maximal therapeutic benefits of 5-HT1A receptor agonists to be realized, underlying the poor clinical effectiveness of currently marketed agents like 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...
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...
which act as mere weak-moderate partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
s.
Rodent studies
In the forced swim test, eptapirone suppresses immobility more robustly than buspirone, ipsapironeIpsapirone
Ipsapirone is a selective 5-HT1A receptor partial agonist of the piperazine and azapirone chemical classes. It has antidepressant and anxiolytic effects.- References :...
, flesinoxan
Flesinoxan
Flesinoxan is a potent and selective 5-HT1A receptor partial/near-full agonist of the phenylpiperazine class. Originally developed as an antihypertensive agent, it was later found to possess antidepressant and anxiolytic effects in animals...
, paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
, and imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
, indicating that it possesses powerful 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;...
effects which may be superior to those of currently available pharmaceuticals. In this test, unlike the other agents screened, buspirone actually increases immobility time with a single administration, while repeated administration decreases it, likely as a result of buspirone's very poor intrinsic activity (~30%) in activating the 5-HT1A receptor.
While high dose paroxetine is able to rival the reduction in immobility induced by eptapirone, it is only able to do so after repeated administration (in contrast to eptapirone which requires only a single dose), suggesting that eptapirone has a more 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...
than other antidepressants as well. Imipramine was unable to match eptapirone or high dose paroxetine's efficacy as greater doses were fatal.
In the conflict procedure
Conflict procedure
The conflict procedure is an experiment widely used in scientific research to quantify anxiety levels through measuring changes in punished/unpunished responding. It is often used to screen drugs for anxiolytic potential....
, eptapirone produces substantial increases in punished responding without affecting unpunished responding, demonstrating marked anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
effects. Furthermore, these effects are more evident than those afforded by buspirone, ipsapirone, and flesinoxan.
Human studies
Eptapirone has been tested in humanHuman
Humans are the only living species in the Homo genus...
s in preclinical trials at an oral
Oral administration
Oral administration is a route of administration where a substance is taken through the mouth.-Terminology:Per os is an adverbial phrase meaning literally from Latin "by mouth" or "by way of the mouth." The expression is used in medicine to describe a treatment that is taken orally. The...
dose
Dose (biochemistry)
A dose is a quantity of something that may impact an organism biologically; the greater the quantity, the larger the dose. In nutrition, the term is usually applied to how much of a specific nutrient is in a person's diet or in a particular food, meal, or dietary supplement...
of 1.5 mg. In these studies, eptapirone reduces body temperature, suppresses REM sleep, increases cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
and growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
levels, and produces 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 including dizziness
Dizziness
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....
and drowsiness while being overall well-tolerated. It peaks rapidly within 30–60 minutes and has an estimated half-life
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...
of two hours, with a total duration of approximately three hours.