title: N-0923, a selective dopamine D2 receptor agonist, is efficacious in rat and monkey models of Parkinson's disease.
abstract: Certain aminotetralins are known to be potent dopamine D2 receptor agonists. N-0923, [-]2-(N-propyl-N-2-thienylethylamino)-5- hydroxytetralin HCl, recognizes the high and low affinity states of the D2 receptor in membranes from bovine caudate with a Klow of 79 nM. The selectivity ratio is D2/D1 = 15 and D2/alpha 2 = 1.4. N-0923 also inhibits dopamine uptake and prolactin secretion, and it is an antagonist at the alpha 2 receptor. N-0923 (3-300 nmol/kg, s.c.) induced dose-dependent contralateral turning behavior in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. The ED50 of 30 nmol/kg was effective for 1 h. The positive enantiomer (N-0924; 300 nmol/kg, s.c.) was without effect. A hemiparkinsonian syndrome was induced in four Macaca nemestrina monkeys by unilateral infusion of the neurotoxin MPTP into the right carotid artery. Video recordings of free-moving behavior revealed bradykinesia, disuse of the contralateral upper limb and turning in a direction ipsilateral to the lesion. N-0923 (3-300 nmol/kg, i.m.) induced contralateral turning behavior, exploratory activity, and contralateral limb usage. The ED50 for turning (30 nmol/kg) was effective for 0.5 h. The potency order for induction of contralateral rotations was (+)-PHNO > N-0923 > bromocriptine. N-0924 (300 nmol/kg, i.m.) was ineffective. We conclude that N-0923 may be useful as a therapeutic agent in the treatment of Parkinson's disease.
authors.affiliation: Department of Pharmacology, Whitby Research, Inc., Richmond, Virginia.
authors.forename: J D
authors.initials: JD
authors.lastname: Belluzzi
authors.forename: E F
authors.initials: EF
authors.lastname: Domino
authors.forename: J M
authors.initials: JM
authors.lastname: May
authors.forename: K S
authors.initials: KS
authors.lastname: Bankiewicz
authors.forename: D A
authors.initials: DA
authors.lastname: McAfee
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology; D004195:Disease Models, Animal; D004292:Dominance, Cerebral / Q000187:drug effects / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology*; D005260:Female; D007273:Injections, Intramuscular; D008254:Macaca nemestrina; D008297:Male; D010078:Oxazines / Q000494:pharmacology; D016627:Oxidopamine / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology*; D011388:Prolactin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D015259:Dopamine Agents; D010078:Oxazines; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C042631:naxagolide; D001971:Bromocriptine; C047508:rotigotine; D016627:Oxidopamine; D011388:Prolactin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine