CHARACTERIZATION OF U-92016A AS A SELECTIVE, ORALLY-ACTIVE, HIGH INTRINSIC ACTIVITY 5-HYDROXYTRYPTAMINE(1A) AGONIST

The purpose of the present study was to characterize U-9201 6A {(+)-R) -2-cyano-N,N-dipropyl-8-amino-6,7 rahydro-3H-benz[e]indole} as a 5-hyd roxytryptamine (5-HT)(1A) receptor agonist and to compare its activity with that of standard 5-HT1A receptor agonists. U-92016A binds with h igh affinity to human 5-HT,, receptors expressed in Chinese hamster ov ary cells (K-i = 0.2 nM). Radioligand binding studies also indicate th at U-92016A is selective for the 5-HT1A receptor over other biogenic a mine receptors. In Chinese hamster ovary cells expressing the human 5H T(1A) receptor, U-92016A decreased the forskolin-induced increase in c yclic AMP synthesis and had an intrinsic activity of 0.82 relative to 5-HT. U-92016A potently decreased rectal temperature in mice. The maxi mum temperature decrease was significantly greater than that observed for 8-hydroxy-di-n-propyl aminotetralin, buspirone, gepirone, ipsapiro ne or flesinoxan. U-92016A also elicited the 5-HT-mediated syndrome in rats and resulted in a dose-related decrease in 5-hydroxytryptophan a ccumulation. The compound also decreased arterial blood pressure in sp ontaneously hypertensive rats and inhibited sympathetic nerve activity in cats. In these assays U-92016A displayed excellent potency and a l ong duration of action. U-92016A also inhibited the firing of dorsal r aphe 5-HT neurons and was active in two social interaction assays. The p.o. bioavailability of U-92016A was calculated to be 45%. Taken toge ther, these data indicate that U-92016A is a metabolically stable, p.o . active 5-HT1A rxeceptor agonist with an exceptionally high degree of intrinsic activity.