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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.

Publication ,  Journal Article
DeWald, HA; Heffner, TG; Jaen, JC; Lustgarten, DM; McPhail, AT; Meltzer, LT; Pugsley, TA; Wise, LD
Published in: Journal of medicinal chemistry
January 1990

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.

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Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

January 1990

Volume

33

Issue

1

Start / End Page

445 / 450

Related Subject Headings

  • Substantia Nigra
  • Stereoisomerism
  • Receptors, Dopamine D2
  • Receptors, Dopamine
  • Rats
  • Oxazines
  • Neurons
  • Motor Activity
  • Molecular Structure
  • Mice
 

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DeWald, H. A., Heffner, T. G., Jaen, J. C., Lustgarten, D. M., McPhail, A. T., Meltzer, L. T., … Wise, L. D. (1990). 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 of Medicinal Chemistry, 33(1), 445–450. https://doi.org/10.1021/jm00163a068
DeWald, H. A., T. G. Heffner, J. C. Jaen, D. M. Lustgarten, A. T. McPhail, L. T. Meltzer, T. A. Pugsley, and L. D. Wise. “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 of Medicinal Chemistry 33, no. 1 (January 1990): 445–50. https://doi.org/10.1021/jm00163a068.
DeWald HA, Heffner TG, Jaen JC, Lustgarten DM, McPhail AT, Meltzer LT, et al. 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 of medicinal chemistry. 1990 Jan;33(1):445–50.
DeWald, H. A., et al. “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 of Medicinal Chemistry, vol. 33, no. 1, Jan. 1990, pp. 445–50. Epmc, doi:10.1021/jm00163a068.
DeWald HA, Heffner TG, Jaen JC, Lustgarten DM, McPhail AT, Meltzer LT, Pugsley TA, Wise LD. 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 of medicinal chemistry. 1990 Jan;33(1):445–450.
Journal cover image

Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

January 1990

Volume

33

Issue

1

Start / End Page

445 / 450

Related Subject Headings

  • Substantia Nigra
  • Stereoisomerism
  • Receptors, Dopamine D2
  • Receptors, Dopamine
  • Rats
  • Oxazines
  • Neurons
  • Motor Activity
  • Molecular Structure
  • Mice