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

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, a...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070714l