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Eptapirone
Systematic (IUPAC) name
4-methyl-2-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-1,2,4-triazine-3,5-dione
Identifiers
CAS number 179756-85-5
ATC code none
PubChem 208928
ChemSpider 181024
Chemical data
Formula C16H23N7O2 
Mol. mass 345.40 g/mol
Pharmacokinetic data
Half life ~2 hours
Therapeutic considerations
Pregnancy cat.  ?
Legal status Uncontrolled
Routes Oral

Eptapirone (F-11,440) is a very potent and highly selective 5-HT1A receptor full agonist of the azapirone and piperazine chemical classes.[1][2] 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.[1]

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 agonists.[1][3][2][4]

Contents

Rodent studies

In the forced swim test, eptapirone suppresses immobility more robustly than buspirone, ipsapirone, flesinoxan, paroxetine, and imipramine, indicating that it possesses powerful antidepressant effects which may be superior to those of currently available pharmaceuticals.[1] 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.[1]

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.[1] Imipramine was unable to match eptapirone or high dose paroxetine's efficacy as greater doses were fatal, likely on account of its lack of selectivity/actions on ion channels.[1]

In the conflict procedure, eptapirone produces substantial increases in punished responding without affecting unpunished responding, demonstrating marked anxiolytic effects.[1] Furthermore, these effects are more evident than those afforded by buspirone, ipsapirone, and flesinoxan.[1]

Human studies

Eptapirone has been tested in humans in preclinical trials at an oral dose of 1.5 mg.[5][6] In these studies, eptapirone reduces body temperature, suppresses REM sleep, increases cortisol and growth hormone levels, and produces side effects like dizziness and drowsiness, while being overall well-tolerated.[5][6] It peaks rapidly within 30-60 minutes and has an estimated half-life of 2 hours, with a total duration of approximately 3 hours.[5][6]

See also

References

  1. ^ a b c d e f g h i Koek W, Patoiseau JF, Assié MB, et al. (October 1998). "F 11440, a potent, selective, high efficacy 5-HT1A receptor agonist with marked anxiolytic and antidepressant potential". The Journal of Pharmacology and Experimental Therapeutics 287 (1): 266–83. PMID 9765347. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9765347. 
  2. ^ a b Prinssen EP, Colpaert FC, Koek W (October 2002). "5-HT1A receptor activation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy". European Journal of Pharmacology 453 (2-3): 217–21. PMID 12398907. http://linkinghub.elsevier.com/retrieve/pii/S0014299902024305. 
  3. ^ Koek W, Vacher B, Cosi C, et al. (May 2001). "5-HT1A receptor activation and antidepressant-like effects: F 13714 has high efficacy and marked antidepressant potential". European Journal of Pharmacology 420 (2-3): 103–12. PMID 11408031. http://linkinghub.elsevier.com/retrieve/pii/S0014299901010111. 
  4. ^ Maurel JL, Autin JM, Funes P, Newman-Tancredi A, Colpaert F, Vacher B (October 2007). "High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity". Journal of Medicinal Chemistry 50 (20): 5024–33. doi:10.1021/jm070714l. PMID 17803293. http://dx.doi.org/10.1021/jm070714l. 
  5. ^ a b c Wilson SJ, Bailey JE, Rich AS, et al. (November 2005). "The use of sleep measures to compare a new 5HT1A agonist with buspirone in humans". Journal of Psychopharmacology (Oxford, England) 19 (6): 609–13. doi:10.1177/0269881105058775. PMID 16272182. http://jop.sagepub.com/cgi/pmidlookup?view=long&pmid=16272182. 
  6. ^ a b c Wilson SJ, Bailey JE, Nutt DJ (June 2005). "Dizziness produced by a potent 5HT(1A) receptor agonist (eptapirone) is not due to postural hypotension". Psychopharmacology 179 (4): 895–6. doi:10.1007/s00213-004-2111-4. PMID 15619110. http://dx.doi.org/10.1007/s00213-004-2111-4. 
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