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

Mov Disord. 1994 Mar;9(2):147-54. doi: 10.1002/mds.870090204.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Bromocriptine / pharmacology
  • Disease Models, Animal
  • Dominance, Cerebral / drug effects
  • Dominance, Cerebral / physiology
  • Dopamine Agents / pharmacology*
  • Female
  • Injections, Intramuscular
  • Macaca nemestrina
  • Male
  • Oxazines / pharmacology
  • Oxidopamine / pharmacology
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / physiopathology*
  • Prolactin / blood
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / drug effects*
  • Receptors, Dopamine D2 / physiology
  • Stereotyped Behavior / drug effects
  • Stereotyped Behavior / physiology
  • Substantia Nigra / drug effects
  • Substantia Nigra / physiopathology
  • Tetrahydronaphthalenes / pharmacology*
  • Thiophenes / pharmacology*

Substances

  • Dopamine Agents
  • Oxazines
  • Receptors, Dopamine D2
  • Tetrahydronaphthalenes
  • Thiophenes
  • naxagolide
  • Bromocriptine
  • rotigotine
  • Oxidopamine
  • Prolactin
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine