S 15535: a highly selective benzodioxopiperazine 5-HT1A receptor ligand which acts as an agonist and an antagonist at presynaptic and postsynaptic sites respectively

Eur J Pharmacol. 1993 Jan 5;230(1):99-102. doi: 10.1016/0014-2999(93)90416-f.


The novel benzodioxopiperazine, S 15535 (4-(benzodioxan-5-yl)1-(indan-2- yl)piperazine), displayed high affinity for 5-HT1A binding sites (1.8 nM) whereas its affinity was 100-fold lower at other 5-HT receptor types, at alpha 1, alpha 2- and beta-adrenoceptors and at dopamine D1 and D2 receptors. In vivo, S 15535 (0.16-10 mg/kg s.c.) acted as an antagonist at postsynaptic 5-HT1A receptors in completely blocking the flat-body posture and hypothermia elicited by the 5-HT1A receptor agonist, 8-OH-DPAT. It had no effect when applied alone. At presynaptic 5-HT1A receptors, S 15535 acted as an agonist in inhibiting striatal accumulation of 5-hydroxytryptophan (0.04-0.63 mg/kg s.c.) and in spiperone reversibly reducing electrical activity of the dorsal raphe nucleus (0.004-0.031 mg/kg i.v.). At doses up to 40.0 mg/kg s.c., S 15535 neither inhibited methylphenidate-induced gnawing nor elicited ptosis suggesting a lack of antagonist properties at, respectively, dopamine D2 receptors and alpha 1-adrenoceptors. In conclusion, S 15535 is a potent 5-HT1A ligand which acts, in vivo, as a highly selective agonist and antagonist at presynaptic and postsynaptic 5-HT1A receptors, respectively.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Blepharoptosis / chemically induced
  • Body Temperature / drug effects
  • Brain Chemistry / drug effects
  • Ligands
  • Male
  • Piperazines / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, alpha / drug effects
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Serotonin / drug effects*
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology*
  • Synapses / drug effects*


  • Ligands
  • Piperazines
  • Receptors, Adrenergic, alpha
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • 1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine
  • 4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine
  • BMY 7378