N-0923, A SELECTIVE DOPAMINE D-2 RECEPTOR AGONIST, IS EFFICACIOUS IN RAT AND MONKEY MODELS OF PARKINSONS-DISEASE

Certain aminotetralins are known to be potent dopamine D, receptor ago nists. N-0923, N-propyl-N-2-thienylethylamino)-5-hydroxy-tetralin HCl, recognizes the high and low affinity states of the D-2 receptor in me mbranes from bovine caudate with a K-low of 79 nM. The selectivity rat io is D-2/D-1 = 15 and D-2/alpha(2) = 1.4. N-0923 also inhibits dopami ne uptake and prolactin secretion, and it is an antagonist at the alph a(2) receptor. N-0923 (3-300 nmol/kg, s.c.) induced dose-dependent con tralateral turning behavior in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. The ED(50) of 30 nmol/kg was effectiv e for 1 h. The positive enantiomer (N-0924; 300 nmol/kg, s.c.) was wit hout effect. A hemiparkinsonian syndrome was induced in four Macaca ne mestrina monkeys by unilateral infusion of the neurotoxin MPTP into th e right carotid artery. Video recordings of free-moving behavior revea led bradykinesia, disuse of the contralateral upper limb and turning i n a direction ipsilateral to the lesion. N-0923 (3-300 nmol/kg, i.m.) induced contralateral turning behavior, exploratory activity, and cont ralateral limb usage. The ED(50) for turning (30 nmol/kg) was effectiv e for 0.5 h. The potency order for induction of contralateral rotation s was (+)-PHNO > N-0923 > bromocriptine. N-0924 (300 nmol/kg, i.m.) wa s ineffective. We conclude that N-0923 may be useful as a therapeutic agent in the treatment of Parkinson's disease.