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

• Published in: European journal of pharmacology 2001-05, Vol.420 (2-3), p.103-112
• Main Authors: KOEK, Wouter, VACHER, Bernard, COSI, Cristina, ASSIE, Marie-Bernadette, PATOISEAU, Jean-Francois, PAUWELS, Petrus J, COLPAERT, Francis C
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Aminopyridines - metabolism; Aminopyridines - pharmacology; Animals; Antidepressive Agents - pharmacology; Binding, Competitive - drug effects; Biological and medical sciences; Buspirone - pharmacology; Colforsin - pharmacology; Cyclic AMP - metabolism; Dose-Response Relationship, Drug; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; HeLa Cells; Humans; Male; Medical sciences; Motor Activity - drug effects; Neuropharmacology; Pharmacology. Drug treatments; Piperazines - pharmacology; Piperidines - metabolism; Piperidines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyridines - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Serotonin - drug effects; Receptors, Serotonin - genetics; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT1; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - metabolism; Serotonin Receptor Agonists - pharmacology; Swimming
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/s0014-2999(01)01011-1

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