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.