Eptapirone (F-11,440) is a very potent and highly selective 5-HT_1A receptor

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 a ...

of the

azapirone Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). Medical uses Azapirones have shown b ...

family. Its affinity for the 5-HT_1A receptor was reported to be 4.8 nM (K_i) (or 8.33 (pK_i)), and its intrinsic activity approximately equal to that of

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...

(i.e., 100%). Eptapirone and related high-efficacy 5-HT_1A full and super agonists such as befiradol and F-15,599 were developed under the hypothesis that the maximum exploitable therapeutic benefits of 5-HT_1A receptor agonists might not be able to be seen without the drugs employed possessing sufficiently high intrinsic activity at the receptor. As 5-HT_1A 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-HT_1A receptor agonists like buspirone and

tandospirone Tandospirone (brand name Sediel) is an anxiolytic and antidepressant drug used in China and Japan, 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 li ...

, which act merely as weak-to-moderate

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

s of the receptor.

Animal studies

In the Porsolt forced swimming test, eptapirone was found to suppress immobility more robustly than buspirone,

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 continues ...

flesinoxan Flesinoxan (DU-29,373) is a potent and selective 5-HT1A receptor partial/near- full agonist of the phenylpiperazine class. Originally developed as a potential antihypertensive drug, flesinoxan was later found to possess antidepressant and anx ...

, 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-HT_1A receptor and/or its preferential activation of 5-HT_1A 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 An anxiolytic (; also antipanic or antianxiety 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 anxiet ...

-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

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...

s in preclinical trials at an

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid ** Oral administration of medicines ** Oral examination (also known as an oral exam or or ...

dose of 1.5 mg. In these studies, eptapirone reduced

body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperatur ...

, prolonged

REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream ...

, increased

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the '' zona fasciculata'' of the adrenal cortex in the adrenal g ...

and

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...

levels, and produced

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, consequence ...

s such as

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

and drowsiness while being overall well tolerated. It peaked rapidly within 30–60 minutes and had an estimated

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

of two hours, with a total duration of approximately three hours.

References

{{Piperazines Aminopyrimidines Piperazines Triazines Imides Lactams Azapirones

Animal studies

Human studies

See also

References