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.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • DeWald, HA; Heffner, TG; Jaen, JC; Lustgarten, DM; McPhail, AT; Meltzer, LT; Pugsley, TA; Wise, LD

Published Date

  • January 1990

Published In

Volume / Issue

  • 33 / 1

Start / End Page

  • 445 - 450

PubMed ID

  • 1967318

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm00163a068


  • eng