N‐0923, a selective dopamine D2 receptor agonist, is efficacious in rat and monkey models of Parkinson's disease

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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/α2 = 1.4. N‐0923 also inhibits dopamine uptake and prolactin secretion, and it is an antagonist at the α2 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 (+)‐PHNON‐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.