title: High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Maurel
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Autin
authors.forename: Philippe
authors.initials: P
authors.lastname: Funes
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: Francis
authors.initials: F
authors.lastname: Colpaert
authors.forename: Bernard
authors.initials: B
authors.lastname: Vacher
mesh_terms: 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