Vol. 287, Issue 1, 266-283, October 1998

F 11440, a Potent, Selective, High Efficacy 5-HT_1A Receptor Agonist with Marked Anxiolytic and Antidepressant Potential

W. Koek, J.-F. Patoiseau, M.-B. Assié, C. Cosi, M. S. Kleven, E. Dupont-Passelaigue, E. Carilla-Durand, C. Palmier, J.-P. Valentin, G. John, P. J. Pauwels, J.-P. Tarayre and F. C. Colpaert

Centre de Recherche Pierre Fabre, Castres Cedex, France

F 11440 (4-methyl-2-[4-(4-(pyrimidin-2-yl)-piperazino)-butyl]-2H,4H-1,2,4-triazin-3,5-dione) was the outcome of a research effort guided by the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT_1A receptors determines the magnitude of their antidepressant and anxiolytic-like effects. The affinity of F 11440 for 5-HT_1A binding sites (pK_i, 8.33) was higher than that of buspirone (pK_i, 7.50), and somewhat lower than that of flesinoxan (pK_i, 8.91). In vivo, F 11440 was 4- to 20-fold more potent than flesinoxan, and 30- to 60-fold more potent than buspirone, in exerting 5-HT_1A agonist activity at pre- and postsynaptic receptors in rats (measured by, for example, its ability to decrease hippocampal extracellular serotonin (5-HT) levels and to increase plasma corticosterone levels, respectively). F 11440 did not have detectable antidopaminergic activity (unlike buspirone, which inhibited all of the directly observable behavioral effects of methylphenidate in rats), showed no evidence of antihistaminergic activity (unlike flesinoxan, which protected against the effects of a histamine aerosol in guinea pigs), and had a 70-fold separation between its 5-HT_1A agonist and alpha-1 adrenergic antagonist properties (measured as the ability to inhibit the methoxamineinduced increase in blood pressure in rats), unlike flesinoxan, which showed a <3-fold separation. In HeLa cells expressing human 5-HT_1A receptors, F 11440 decreased the forskolin-induced increase in AMP, and, based on its maximal effect, was found to have an intrinsic activity of 1.0 relative to that of 5-HT, which was significantly higher than that of buspirone (0.49), ipsapirone (0.46) and flesinoxan (0.93). Consistent with the aforementioned hypothesis, F 11440 produced anxiolytic- and antidepressant-like effects in animal models (i.e., increased punished responding in a pigeon conflict procedure and decreased immobility in a rat forced swimming test, respectively) that were more substantial than those of buspirone, ipsapirone and flesinoxan. Thus, F 11440, shown here to be a potent, selective, high efficacy 5-HT_1A receptor agonist, appears to have the potential to exert marked anxiolytic and antidepressant activity in humans.