Anpirtoline, a novel, highly potent 5-HT1B receptor agonist with antinociceptive/antidepressant-like actions in rodents

Br J Pharmacol. 1992 Mar;105(3):732-8. doi: 10.1111/j.1476-5381.1992.tb09047.x.

Abstract

1. The purpose of the present study was to relate the effects of the novel drug, anpirtoline, on 5-hydroxytryptamine (5-HT) receptor subtypes to its antinociceptive and antidepressant-like actions in rodents. 2. Binding assays with rat brain membranes have shown that anpirtoline bound with a much higher affinity to 5-HT1B receptor (Ki = 28 nM) than to 5-HT1A (Ki = 150 nM) and 5-HT2 (Ki = 1.49 microM) receptors. 3. Like 5-HT, anpirtoline concentration-dependently inhibited forskolin-stimulated adenylate cyclase activity in homogenates from the rat substantia nigra. Both effects were not additive, and could be prevented by 5-HT1B receptor antagonists such as propranolol and penbutolol. 4. In superfused rat and pig brain cortex slices preincubated with [3H]-5-HT, the electrically evoked tritium overflow was inhibited by anpirtoline and 5-HT. Whereas 5-HT was equipotent in both tissues (EC50 = 69 nM), anpirtoline was markedly less potent in pig brain cortex slices (EC50 = 1190 nM) than in rat brain cortex slices (EC50 = 55 nM). The concentration-response curve for anpirtoline was shifted to the right by metitepine in both preparations. 5. In the social behaviour deficit test, anpirtoline and trifluoromethylphenyl-piperazine were effective in reversing the isolation-induced impairments in mice, an effect shown only by compounds with agonist properties at the 5-HT1B receptor. 6. In the electrostimulated pain test using mice, anpirtoline dose-dependently increased the pain threshold with an ED50 of 0.52 mg kg-1, i.p. The antinociceptive activity of anpirtoline was abolished by pretreatment with cyproheptadine or propranolol.7. In the forced swimming test in rats, anpirtoline induced a dose-related increase in swimming activity. With an ED50 value of 4.6mgkg-1, i.p., anpirtoline was 4 times more potent than the two standard compounds imipramine and desipramine. The decrease of immobility time or the increase of active periods in this model of behavioural despair is suggested to be characteristic of antidepressant drugs.8. Anpirtoline exhibits both antinociceptive and antidepressant-like activities in animals. It is probable that anpirtoline elicits these pharmacological effects via its agonist effect on 5-HT1B and 5-HT1A receptors.

MeSH terms

  • Adenylyl Cyclase Inhibitors
  • Analgesics / pharmacology*
  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain Chemistry / drug effects
  • Electric Stimulation
  • Female
  • In Vitro Techniques
  • Male
  • Mice
  • Piperidines / pharmacology*
  • Pyridines / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / physiology*
  • Social Behavior
  • Social Isolation
  • Swine

Substances

  • Adenylyl Cyclase Inhibitors
  • Analgesics
  • Antidepressive Agents
  • Piperidines
  • Pyridines
  • Receptors, Serotonin
  • anpirtoline