Dopamine agonists related to 3-allyl-6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzaz epi ne-7, 8-diol. 6-Position modifications

J Med Chem. 1987 Jan;30(1):35-40. doi: 10.1021/jm00384a006.

Abstract

The N-allyl derivative (SK&F 85174) of 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-diol (SK&F 82526) retains the DA-1 agonist potency of the latter compound but unlike the parent also shows substantial DA-2 agonist activity. In a previous study of N-substituted benzazepines these combined agonist effects were shown to be uniquely associated with the N-allyl group. A continuation of this research has examined dependency of combined DA-2/DA-1 agonist activities on 6-position modification with the specific objective of developing an agonist with maximum effectiveness and potency at the DA-2 receptor subtype. DA-2 agonist activity was measured in a rabbit ear artery assay, and DA-1 agonist activity was determined in an adenylate cyclase assay. Replacing chloro with bromo retains the activity pattern and the potency of the chloro compound; replacement with a hydrogen causes a decrease of both DA-1 and DA-2 receptor activating potency. Introduction of a 6-methyl group causes loss of DA-2 agonist activity and reduction in DA-1 agonist potency. Substitution with a 6-fluoro provides the best balance of DA-2 and DA-1 agonist activities; this compound was moderately potent in both assays.

Publication types

  • Comparative Study

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Benzazepines / chemical synthesis*
  • Benzazepines / pharmacology
  • Dopamine / physiology*
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Rabbits
  • Receptors, Dopamine / drug effects
  • Receptors, Dopamine / physiology*
  • Structure-Activity Relationship

Substances

  • Benzazepines
  • Indicators and Reagents
  • Receptors, Dopamine
  • SK&F 85174
  • Adenylyl Cyclases
  • Dopamine