5-HT1A receptor activation and antidepressant-like effects: F 13714 has high efficacy and marked antidepressant potential

Wouter Koek, Bernard Vacher, Cristina Cosi, Marie Bernadette Assié, Jean François Patoiseau, Petrus J. Pauwels, Francis C. Colpaert

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

To examine further the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT1A receptors determines the magnitude of their psychotropic activity, we studied the relationship between the maximal receptor activation produced by various 5-HT1A receptor ligands and their antidepressant-like effects (i.e., decreased immobility in the forced swimming test in rats). Using three different in vitro assays suitable to measure differences among high, intermediate, and low efficacy 5-HT1A receptor agonists, ligands were identified with intrinsic activities ranging from low-negative (i.e., the inverse agonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane- carboxamide (WAY 100635)) to high-positive (i.e., 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methyl-6-methylamino-pyridin-2- ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone (F 13714)). In addition, novel compounds with intermediate intrinsic activity, like buspirone, but with high selectivity for 5-HT1A receptors, unlike buspirone, were identified. The maximal effects of the 5-HT1A receptor ligands in the forced swimming test correlated positively (rS = 0.91, P < 0.005) with the rank order of their intrinsic activity at 5-HT1A receptors. This relationship constitutes evidence that the magnitude of the psychotropic activity of 5-HT1A receptor ligands is a positive function of their intrinsic activity at the receptor, and suggests that F 13714, which had maximal effects in the forced swimming test significantly larger than any of the other compounds examined here, did so because of its higher intrinsic activity at 5-HT1A receptors.

Original languageEnglish (US)
Pages (from-to)103-112
Number of pages10
JournalEuropean Journal of Pharmacology
Volume420
Issue number2-3
DOIs
StatePublished - May 25 2001
Externally publishedYes

Keywords

  • (Rat)
  • 5-HT receptor
  • Antidepressant
  • Forced swimming test
  • Intrinsic activity
  • [S]GTPγS binding
  • cAMP

ASJC Scopus subject areas

  • Pharmacology

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