Characterization of U-92016A as a selective, orally active, high intrinsic activity 5-hydroxytryptamine1A agonist.
The purpose of the present study was to characterize U-92016A [(+)-R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e] indole] as a 5-hydroxytryptamine (5-HT)1A receptor agonist and to compare its activity with that of standard 5-HT1A receptor agonists. U-92016A binds with high affinity to human 5-HT1A receptors expressed in Chinese hamster ovary cells (Ki = 0.2 nM). Radioligand binding studies also indicate that U-92016A is selective for the 5-HT1A receptor over other biogenic amine receptors. In Chinese hamster ovary cells expressing the human 5HT1A receptor, U-92016A decreased the forskolin-induced increase in cyclic AMP synthesis and had an intrinsic activity of 0.82 relative to 5-HT. U-92016A potently decreased rectal temperature in mice. The maximum temperature decrease was significantly greater than that observed for 8-hydroxy-di-n-propyl aminotetralin, buspirone, gepirone, ipsapirone or flesinoxan. U-92016A also elicited the 5-HT-mediated syndrome in rats and resulted in a dose-related decrease in 5-hydroxytryptophan accumulation. The compound also decreased arterial blood pressure in spontaneously hypertensive rats and inhibited sympathetic nerve activity in cats. In these assays U-92016A displayed excellent potency and a long duration of action. U-92016A also inhibited the firing of dorsal raphe 5-HT neurons and was active in two social interaction assays. The p.o. bioavailability of U-92016A was calculated to be 45%. Taken together, these data indicate that U-92016A is a metabolically stable, p.o. active 5-HT1A receptor agonist with an exceptionally high degree of intrinsic activity.
Upjohn Company, Kalamazoo, Michigan.
R B
RB
McCall
A G
AG
Romero
M J
MJ
Bienkowski
D W
DW
Harris
J C
JC
McGuire
M F
MF
Piercey
M E
ME
Shuck
M W
MW
Smith
K A
KA
Svensson
P J
PJ
Schreur
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001483:Base Sequence; D001682:Biological Availability; D001831:Body Temperature / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D014151:Anti-Anxiety Agents; D007211:Indoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C082405:U 92016A; D006916:5-Hydroxytryptophan