Eptapirone and related high-efficacy 5-HT1A full and super agonists such asbefiradol andF-15,599 were developed under the hypothesis that the maximum exploitable therapeutic benefits of 5-HT1A receptor agonists might not be able to be seen without the drugs employed possessing sufficiently high intrinsic activity at the receptor. As 5-HT1A receptor agonism, based on animal and other research, looked extremely promising for the treatment ofdepression from a theoretical perspective, this idea was developed as a potential explanation for the relatively modest clinical effectiveness seen with already available 5-HT1A receptor agonists likebuspirone andtandospirone, which act merely as weak-to-moderatepartial agonists of the receptor.[1][2][3][4][5]
In thePorsolt forced swimming test, eptapirone was found to suppress immobility more robustly than buspirone,ipsapirone,flesinoxan,paroxetine, andimipramine, which was suggestive of strong antidepressant-like effects.[1] In this assay, unlike the other drugs screened, buspirone actuallyincreased 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-HT1A receptor and/or it's preferential activation of 5-HT1A somatodendritic autoreceptors over postsynaptic receptors.[1]
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.[1] 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.[1]
In theconflict procedure, eptapirone produced substantial increases in punished responding without affecting unpunished responding, which was suggestive of markedanxiolytic-like effects.[1] In addition, the efficacy of eptapirone in this assay was more evident than that of buspirone, ipsapirone, and flesinoxan.[1]
^abPrinssen 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.doi:10.1016/S0014-2999(02)02430-5.PMID12398907.
^Celada P, Bortolozzi A, Artigas F (September 2013). "Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research".CNS Drugs.27 (9):703–16.doi:10.1007/s40263-013-0071-0.hdl:10261/88633.PMID23757185.S2CID31931009.
^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.doi:10.1016/S0014-2999(01)01011-1.PMID11408031.
^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.PMID17803293.
^abcWilson 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.19 (6):609–13.doi:10.1177/0269881105058775.PMID16272182.S2CID34590219.
^abcWilson 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.PMID15619110.S2CID27804035.
