Novel benzodioxopiperazines acting as antagonists at postsynaptic 5-HT1A receptors and as agonists at 5-HT1A autoreceptors: a comparative pharmacological characterization with proposed 5-HT1A antagonists

J Pharmacol Exp Ther. 1994 Jan;268(1):337-52.

Abstract

The novel benzodioxopiperazines [4-(benzodioxan-5-yl)1-[2- (benzocyclobutane-1-yl)ethyl]piperazine] (S 14489), [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine)] (S 15535) and [4-(benzodioxan-5-yl)1-[2(indan-1-yl)ethyl]piperazine (S15931) competitively displaced the binding of [3H]-8-OH-DPAT at serotonin (5-HT)1A receptors with affinities (pKis) of 9.2, 8.8 and 8.9, respectively. These values compared favorably with those of the structurally related eltoprazine (8.0) and the proposed 5-HT1A antagonists NAN-190 (9.2), MDL 73005 EF (8.9), SDZ 216-525 (8.8), BMY 7378 (8.7), (-)-tertatolol (8.1), (-)-alprenolol (7.7), WAY 100,135 (7.5) and spiperone (6.9). The affinities of S 14489, S 15535 and S 15931 for other 5-HT receptor types (5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3) were about 50 to 1000-fold lower. The spontaneous tail-flicks, flat-body posture and hypothermia mediated by an action of the 5-HT1A agonist 8-OH-DPAT at postsynaptic 5-HT1A receptors were dose-dependently and completely antagonized by S 14489, S 15535 and S15931 at doses of 0.63 to 10.0 and 2.5 to 40.0 mg/kg for s.c. and oral administration, respectively. They did not induce these responses alone, and in their presence, dose-response curves for 8-OH-DPAT were shifted in parallel to the right without loss of maximal effect. By contrast, eltoprazine, MDL 73005 EF, BMY 7378 and NAN-190 behaved as "partial" agonists and only incompletely antagonized the actions of 8-OH-DPAT in these tests. At 5-HT1A autoreceptors, S 14489, S 15535 and S 15931 acted as agonists in inhibiting striatal 5-hydroxytryptophan accumulation (0.16-2.5 mg/kg, s.c.) and in abolishing the electrical activity of the dorsal raphe nucleus (0.005-0.100 mg/kg, i.v.). Eltoprazine, BMY 7378, NAN-190 and MDL 73005 EF also behaved as agonists at these 5-HT1A autoreceptors, whereas WAY 100,135, spiperone, (-)-tertatolol, (-)-alprenolol and SDZ 216-525 inhibited neither accumulation nor firing. WAY 100,135 and spiperone antagonized the inhibition of DRN firing induced by S 14489, S 15535 and S 15931. The affinity of 15535 for dopamine D1 and D2 receptors, as well as for beta-, alpha 1- and alpha 2-adrenoceptors, was > 100-fold lower than its affinity for 5-HT1A receptors. Further, in vivo, at doses of 10.0 to 40.0 mg/kg, s.c., it showed minimal activity in tests of dopamine D2 (and D1) receptor-mediated activity. Similarly, in vivo, S 15535 was weakly active in a test of alpha 1-adrenoceptor-mediated activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Publication types

  • Comparative Study

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Administration, Oral
  • Animals
  • Corpus Striatum / metabolism
  • Cross-Linking Reagents
  • Dioxanes / administration & dosage
  • Dioxanes / metabolism
  • Dioxanes / pharmacology
  • Guinea Pigs
  • In Vitro Techniques
  • Male
  • Neurons / metabolism
  • Neurons / physiology
  • Piperazines / administration & dosage
  • Piperazines / metabolism
  • Piperazines / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic / drug effects
  • Receptors, Dopamine / drug effects
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists* / pharmacology*
  • Serotonin Receptor Agonists / pharmacology*
  • Synapses / metabolism

Substances

  • Cross-Linking Reagents
  • Dioxanes
  • Piperazines
  • Receptors, Adrenergic
  • Receptors, Dopamine
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • 4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine
  • S 14489
  • S 15931
  • eltoprazine
  • 8-Hydroxy-2-(di-n-propylamino)tetralin