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.

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…348 Rotigotine is a nonergot, lipid soluble aminotetralin derivative with a strong structural resemblance to dopamine. 349 The drug activates D 3 , D 2 , and D 1 dopamine receptors and has motor benefits in animal models of PD. It has a short halflife when administered by mouth due to extensive first-pass hepatic clearance.…”

Safety, Tolerability, and Efficacy of Continuous Transdermal Dopaminergic Stimulation with Rotigotine Patch in Early-Stage Idiopathic Parkinson Disease

“…Rotigotine was effective in a series of preclinical studies in animal models of Parkinson disease. 15,16 Rotigotine is formulated as a transdermal system, a patch, to provide continuous drug delivery that may provide more stable plasma concentrations of a dopaminergic agonist (compared with orally administered drugs) with once-daily dosing for the treatment of patients with early-stage Parkinson disease.…”

Rotigotine transdermal patch in the treatment of Parkinson’s disease and restless legs syndrome

“…The lipophilic nature of rotigotine lends itself to use in a transdermal system [19]. Previous reports of N-0437 refer to a racemic mixture; N-0923 is the (-) enantiomer [20]. (-)-N0437 (rotigotine) is effective in nanomolar concentrations and showed a 150-fold greater potency than (+)-N0437 [21].…”

“…In vitro studies with bovine caudate found high affinity equilibrium constants for D 2 and D 1 receptors of 0.3 and 3.0 nmol/l and low affinity constants of 79 and 1160 nmol/l, respectively [20]. Antagonist properties have also been described at α2-adrenergic receptors, with an apparent dissociation constant (K i ) of 110 nmol/l [9,20], a property that distinguishes rotigotine from other D 2 agonists and may reduce the risk of postural hypotension [20]. Rotigotine acts as an agonist at 5HT 1A receptors and displays antidepressant properties in a rat experimental model [20,23].…”

“…Rotigotine D 2 and D 1 receptor affinity is 20-and 100-fold less than D 3 affinity, respectively [7]. In vitro studies with bovine caudate found high affinity equilibrium constants for D 2 and D 1 receptors of 0.3 and 3.0 nmol/l and low affinity constants of 79 and 1160 nmol/l, respectively [20]. Antagonist properties have also been described at α2-adrenergic receptors, with an apparent dissociation constant (K i ) of 110 nmol/l [9,20], a property that distinguishes rotigotine from other D 2 agonists and may reduce the risk of postural hypotension [20].…”