Synthesis and Dopamine Agonist Properties of (+-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol and Its Enantiomers

J Med Chem. 1990 Jan;33(1):445-50. doi: 10.1021/jm00163a068.

Abstract

The dopamine agonist profile of (+-)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol (16a) and its enantiomers (16b-c) was examined. Racemic 16a exhibited moderate affinity for the dopamine (DA) D2 receptor labeled with the DA antagonist ligand [3H]haloperidol and moderate in vivo activity; it attenuated gamma-butyrolactone-stimulated DA synthesis, decreased DA neuronal firing of substantia nigra DA neurons, and inhibited exploratory locomotor activity in rats, a profile consistent with a DA autoreceptor agonist mechanism of action. The (+)-enantiomer 16b possessed greater DA receptor affinity with the agonist ligand [3H]-N-propylnorapomorphine than with the antagonist ligand. In rats it potently inhibited DA synthesis and neuronal firing and also inhibited exploratory locomotion. The (-)-enantiomer, on the other hand, did not have significant activity in any of these tests. This profile indicates that like many other rigid DA agonists, the dopaminergic activity resides in one enantiomer, in this case the (+)-enantiomer 16b. On the basis of single-crystal X-ray analysis of a key intermediate, the absolute configuration of 16b was found to be 4aR, 10bR.

MeSH terms

  • Animals
  • Benzopyrans / chemical synthesis
  • Benzopyrans / metabolism
  • Benzopyrans / pharmacology*
  • Cell Membrane
  • Chemical Phenomena
  • Chemistry
  • Corpus Striatum / metabolism
  • Dihydroxyphenylalanine / biosynthesis
  • Dopamine / biosynthesis
  • Dopamine Agents*
  • Electrophysiology
  • Haloperidol / metabolism
  • Male
  • Mice
  • Molecular Structure
  • Motor Activity / drug effects
  • Neurons / physiology
  • Oxazines / chemical synthesis
  • Oxazines / metabolism
  • Oxazines / pharmacology*
  • Rats
  • Receptors, Dopamine / drug effects
  • Receptors, Dopamine / metabolism
  • Receptors, Dopamine D2
  • Stereoisomerism
  • Substantia Nigra / physiology

Substances

  • Benzopyrans
  • Dopamine Agents
  • Oxazines
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • 3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol
  • Dihydroxyphenylalanine
  • Haloperidol
  • Dopamine