U-66444B and U-68553B, potent autoreceptor agonists at dopaminergic cell bodies and terminals

MF Piercey, PA Broderick, WE Hoffmann and GD Vogelsang

Central Nervous System Research, Upjohn Company, Kalamazoo, Michigan.

U-66444B was evaluated for pre- and postsynaptic effects in dopaminergic (DA) cell body and nerve terminal regions of chloral hydrate anesthetized rats. U-66444B depressed DA neurons in substantia nigra pars compacta and ventral tegmental area with a potency three times that for apomorphine. With a sufficient dose, cells were completely silenced. Activity was found to reside principally in the (+)-stereoisomer, U-68553B. The effects of U-66444B and U-68553B were reversed by 0.1 mg/kg haloperidol. Apomorphine, but not U-66444B nor U- 68553B, depressions were accompanied by rapid tachyphylaxis. After 2 wk of U-66444B 0.6 mg/kg/day, potency was not significantly affected. By using in vivo voltammetry, 100 micrograms/kg U-68553B produced a depression in DA release that was more dramatic and more prolonged than that for 500 micrograms/kg apomorphine. On DA postsynaptic receptors, iontophoretic U-66444B and apomorphine were approximately equipotent in depressing caudate neuron firing. It is concluded that U-66444B and its active enantiomer, U-68553B, are more potent, longer acting and possibly more selective as DA autoreceptor agonists than apomorphine. The propensity to produce tolerance appears weak.

Volume 254, Issue 2, pp. 369-374, 08/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics