Eptapirone

Eptapirone

Systematic (IUPAC) name
4-methyl-2-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-1,2,4-triazine-3,5-dione
Clinical data
Legal status	Uncontrolled
Routes of administration	Oral
Pharmacokinetic data
Biological half-life	2 hours
Identifiers
CAS Number	179756-85-5
ATC code	none
PubChem	CID: 208928
ChemSpider	181024
UNII	3M824XRO8N Y
Chemical data
Formula	C16H23N7O2
Molecular mass	345.40 g/mol
SMILES Cn1c(=O)cnn(c1=O)CCCCN2CCN(CC2)c3ncccn3
InChI InChI=1S/C16H23N7O2/c1-20-14(24)13-19-23(16(20)25)8-3-2-7-21-9-11-22(12-10-21)15-17-5-4-6-18-15/h4-6,13H,2-3,7-12H2,1H3 Key:NMYAHEULKSYAPP-UHFFFAOYSA-N

Eptapirone (F-11,440) is a very potent and highly selective 5-HT_1A receptor full agonist of the azapirone 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 (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, 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-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-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.

See also

• Befiradol
• F-15,599