Dopamine receptor agonist activity of some 5-(2-aminoethyl)carbostyril derivatives

J Med Chem. 1985 Dec;28(12):1803-10. doi: 10.1021/jm00150a010.

Abstract

The potency of beta-adrenoreceptor agonists, e.g., isoproterenol, is strikingly increased by substitution of the meta catecholic hydroxyl group with the NH group of a carbostyril system. To explore the possibility that comparable potency enhancement might occur upon similar modification of the catechol ring of dopamine, a series of 5-(2-aminoethyl)carbostyril derivatives was prepared and examined for D-1 and D-2 dopamine receptor-stimulating activity. Only the parent compound, 5-(2-aminoethyl)-8-hydroxycarbostyril (2), produced measurable activation of dopamine-sensitive adenylate cyclase (29% at a concentration of 10 microM). Some of the compounds, however, did produce significant activity in tests, namely displacement of [3H]spiroperidol binding from bovine pituitary homogenate and an isolated perfused rabbit ear artery preparation, that measure interaction with D-2 receptors. Potency of the carbostyrils was enhanced by 8-hydroxylation and by appropriate substitution of the amino group of the ethylamine side chain. The most potent member of the series was 8-hydroxy-5-[2-[[2-(4-hydroxyphenyl)ethyl]-n-propylamino]ethyl] carbostyril (16b). This compound was about 3 times more effective than dopamine in the D-2 receptor tests. Clearly, the results of this study indicate that potency of dopamine receptor agonists is not increased by carbostyril replacement of the m-hydroxyl as is noted with the beta-adrenergic receptor agonists.

Publication types

  • Comparative Study

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Arteries / physiology
  • Binding, Competitive
  • Cattle
  • Caudate Nucleus / enzymology
  • Chemical Phenomena
  • Chemistry
  • Dopamine / pharmacology
  • Ear / blood supply
  • Hydroxyquinolines / chemical synthesis
  • Hydroxyquinolines / pharmacology*
  • Pituitary Gland, Anterior / metabolism
  • Rabbits
  • Rats
  • Receptors, Dopamine / drug effects
  • Receptors, Dopamine / physiology*
  • Spiperone / metabolism
  • Vasoconstriction / drug effects

Substances

  • Hydroxyquinolines
  • Receptors, Dopamine
  • Spiperone
  • Adenylyl Cyclases
  • Dopamine