Potential antidepressant properties of SR 57746A, a novel compound with selectivity and high affinity for 5-HT1A receptors

Luigi Cervo, Caterina Bendotti, Gianluca Tarizzo, Alfredo Cagnotto, Malgorzata Skorupska, Tiziana Mennini, Rosario Samanin

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

SR 57746A, 4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6-tetrahydropyridine HCl, was studied for its specific 5-HT1A receptor agonist action and antidepressant-like effects in the rat. The compound showed a high affinity for 5-HT1A specific binding sites in the rat hippocampus (IC50 3 nM), moderate affinity (10-7-10-6 M) for dopamine D2 receptor, 5-HT uptake, 5-HT2 and α1-adrenoceptor binding sites and practically no effect on binding sites of monoamine, GABAA, benzodiazepine and histamine receptors. It inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes at concentrations of 10-6 and 10-5 M. The effect of 10-6 M SR 57746A on forskolin-stimulated adenylate cyclase activity was completely antagonized by 10-6 M (-)-propranolol. Administered per os as a three-dose course to rats, SR 57746A significantly increased struggling in the forced swimming test at doses from 0.3 to 3 mg/kg. Single doses had no such effect. The effect of a three-dose course with 1 mg/kg SR 57746A on rats' struggling was antagonized by pretreatment with 5 mg/kg i.p. metergoline, a non-selective 5-HT receptor antagonist, and by 20 mg/kg i.p. (-)-propranolol, an antagonist at 5-HT1 receptors. Three oral doses of 100 mg/kg parachlorophenylalanine, an inhibitor of 5-HT synthesis, and 100 mg/kg i.p. (±)-sulpride, an antagonist at dopamine D2 receptors, also antagonized the effect of SR 57746A in the forced swimming test. The results show that SR 57746A has selectivity and high affinity for 5-HT1A receptors. The compound is a full agonist at this receptor and shows an antidepressant-like effect in the forced swimming test by a mechanism which seems to involve presynaptic 5-HT1A receptors and a permissive role of brain dopamine D2 receptors.

Original languageEnglish
Pages (from-to)139-147
Number of pages9
JournalEuropean Journal of Pharmacology
Volume253
Issue number1-2
DOIs
Publication statusPublished - Feb 21 1994

Fingerprint

Receptor, Serotonin, 5-HT1A
Antidepressive Agents
Dopamine D2 Receptors
Binding Sites
Colforsin
GABA-A Receptors
Adenylyl Cyclases
Propranolol
Serotonin
Serotonin 5-HT1 Receptors
Metergoline
Serotonin 5-HT1 Receptor Agonists
Histamine Receptors
Serotonin Antagonists
Serotonin Receptors
Adrenergic Receptors
Inhibitory Concentration 50
xaliproden
Hippocampus
Membranes

Keywords

  • 5-HT receptor
  • Adenylate cyclase activity
  • Antidepressant activity
  • Forced swimming test
  • SR 57746A (4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6-tetrahydropyridine HCl)

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Potential antidepressant properties of SR 57746A, a novel compound with selectivity and high affinity for 5-HT1A receptors. / Cervo, Luigi; Bendotti, Caterina; Tarizzo, Gianluca; Cagnotto, Alfredo; Skorupska, Malgorzata; Mennini, Tiziana; Samanin, Rosario.

In: European Journal of Pharmacology, Vol. 253, No. 1-2, 21.02.1994, p. 139-147.

Research output: Contribution to journalArticle

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AB - SR 57746A, 4-(3-trifluoromethylphenyl)-N-[2-(naphth-2-yl)ethyl]-1,2,3,6-tetrahydropyridine HCl, was studied for its specific 5-HT1A receptor agonist action and antidepressant-like effects in the rat. The compound showed a high affinity for 5-HT1A specific binding sites in the rat hippocampus (IC50 3 nM), moderate affinity (10-7-10-6 M) for dopamine D2 receptor, 5-HT uptake, 5-HT2 and α1-adrenoceptor binding sites and practically no effect on binding sites of monoamine, GABAA, benzodiazepine and histamine receptors. It inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes at concentrations of 10-6 and 10-5 M. The effect of 10-6 M SR 57746A on forskolin-stimulated adenylate cyclase activity was completely antagonized by 10-6 M (-)-propranolol. Administered per os as a three-dose course to rats, SR 57746A significantly increased struggling in the forced swimming test at doses from 0.3 to 3 mg/kg. Single doses had no such effect. The effect of a three-dose course with 1 mg/kg SR 57746A on rats' struggling was antagonized by pretreatment with 5 mg/kg i.p. metergoline, a non-selective 5-HT receptor antagonist, and by 20 mg/kg i.p. (-)-propranolol, an antagonist at 5-HT1 receptors. Three oral doses of 100 mg/kg parachlorophenylalanine, an inhibitor of 5-HT synthesis, and 100 mg/kg i.p. (±)-sulpride, an antagonist at dopamine D2 receptors, also antagonized the effect of SR 57746A in the forced swimming test. The results show that SR 57746A has selectivity and high affinity for 5-HT1A receptors. The compound is a full agonist at this receptor and shows an antidepressant-like effect in the forced swimming test by a mechanism which seems to involve presynaptic 5-HT1A receptors and a permissive role of brain dopamine D2 receptors.

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