High-Efficacy 5-HT1A Agonists for Antidepressant Treatment:  A Renewed Opportunity

• Published in: Journal of medicinal chemistry 2007-10, Vol.50 (20), p.5024-5033
• Main Authors: Maurel, Jean Louis, Autin, Jean-Marie, Funes, Philippe, Newman-Tancredi, Adrian, Colpaert, Francis, Vacher, Bernard
• Format: Article
• Language: English
• Subjects: Animals; Antidepressive Agents - chemical synthesis; Antidepressive Agents - chemistry; Antidepressive Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Humans; Medical sciences; Motor Activity - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Radioligand Assay; Rats; Serotonin 5-HT1 Receptor Agonists; Serotoninergic system; Stereotyped Behavior - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070714l

We report the discovery of novel 5-HT1A receptor agonists and describe the process that led to the antidepressant candidate 9 (F 15599). 9 has nanomolar affinity for 5-HT1A binding sites and is over 1000-fold selective with respect to the other 5-HT1 receptor subtypes, 5-HT2 - 7 receptor families, and also numerous GPCRs, transporters, ion channels, and enzymes. In a cellular model of signal transduction, 9 activates h5-HT1A receptors with an efficacy superior to that of the prototypical 5-HT1A agonist (±)-8-OH-DPAT and comparators undergoing clinical trials. After acute oral administration in rats, 9 totally reverses immobility in the forced swimming test and produces behaviors characteristic of 5-HT1A receptor activation. However, these effects occurred at widely separated doses, suggesting that 9 discriminates between distinct populations of 5-HT1A receptors. While the clinical relevance of these observations is still unknown, this opens new perspectives for the treatment of depressive disorders.