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, 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.
Maurel
Jean Louis
JL
Task Force Chemistry, Medicinal Chemistry 1 Division, Neurobiology 2 Division, and Toulouse ISTMT 2, Pierre Fabre Research Center, 17 avenue Jean Moulin, 81106 Castres Cedex, France.
Autin
Jean-Marie
JM
Funes
Philippe
P
Newman-Tancredi
Adrian
A
Colpaert
Francis
F
Vacher
Bernard
B
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D058825:Serotonin 5-HT1 Receptor Agonists; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship