title: U-66444B and U-68553B, potent autoreceptor agonists at dopaminergic cell bodies and terminals.
abstract: 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.
authors.affiliation: Central Nervous System Research, Upjohn Company, Kalamazoo, Michigan.
authors.forename: M F
authors.initials: MF
authors.lastname: Piercey
authors.forename: P A
authors.initials: PA
authors.lastname: Broderick
authors.forename: W E
authors.initials: WE
authors.lastname: Hoffmann
authors.forename: G D
authors.initials: GD
authors.lastname: Vogelsang
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D004347:Drug Interactions; D004594:Electrophysiology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009411:Nerve Endings / Q000187:drug effects; D043803:Phenalenes; D011083:Polycyclic Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D015259:Dopamine Agents; D043803:Phenalenes; D011083:Polycyclic Compounds; D011954:Receptors, Dopamine; C065347:alentamol; D006220:Haloperidol; D001058:Apomorphine; D004298:Dopamine