F-11440, A POTENT, SELECTIVE, HIGH EFFICACY 5-HT1A RECEPTOR AGONIST WITH MARKED ANXIOLYTIC AND ANTIDEPRESSANT POTENTIAL

F 11440 -piperazino)-butyl]-2H,4H-1,2,4-triazin-3,5-dione) was the out come of a research effort guided by the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT1A receptors determines t he magnitude of their antidepressant and anxiolytic-like effects. The affinity of F 11440 for 5-HT1A 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 pote nt than flesinoxan, and 30- to 60-fold more potent than buspirone, in exerting 5-HT1A agonist activity at pre- and postsynaptic receptors in rats (measured by, for example, its ability to decrease hippocampal e xtracellular serotonin (5-HT) levels and to increase plasma corticoste rone levels, respectively). F 11440 did not have detectable antidopami nergic 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 prote cted against the effects of a histamine aerosol in guinea pigs), and h ad a 70-fold separation between its 5-HT1A agonist and alpha-1 adrener gic antagonist properties (measured as the ability to inhibit the meth oxamine-induced increase in blood pressure in rats), unlike flesinoxan , which showed a <3-fold separation. In HeLa cells expressing human 5- HT1A receptors, F 11440 decreased the forskolin-induced increase in AM P, and, based on its maximal effect, was found to have an intrinsic ac tivity 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 anx iolytic- and antidepressant-like effects in animal models (i.e., incre ased 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-HT1A r eceptor agonist, appears to have the potential to exert marked anxioly tic and antidepressant activity in humans.