Synthesis, resolution, and preliminary evaluation of trans-2-amino-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes and related derivatives as dopamine receptors ligands

J Med Chem. 1996 Oct 11;39(21):4238-46. doi: 10.1021/jm960318v.

Abstract

The present work reports the synthesis of enantiomeric pairs of the trans-2-amino-6-hydroxy-1-phenyl-2,3-dihydro-1H-indene [(+)-14a, (-)-14a] and trans-2-amino-5-hydroxy-1-phenyl-2,3-dihydro-1 H-indene [(+)-14b, (-)-14b] and their N,N-di-n-propyl [(+)-and (-)-15a,b], N-methyl-N-allyl [(+)-and (-)-16a,b], and N-methyl-N-n-propyl [(+) and (-)-17a,b] derivatives obtained by a combination of stereospecific reactions and optical resolution. The new compounds were evaluated for their affinity at the dopamine D1 and D2 receptors. The amines (+)- and (-)-14a, incorporating the D1 pharmacophore 2-phenyl-2-(3-hydroxyphenyl)ethylamine in a trans extended conformation, and their derivatives displayed D1 and D2 affinity in the nanomolar range. On the other hand, the enantiomers (+)- and (-)-14b, (+)- and (-)-15b displayed high affinity and selectivity for the D1 receptor. In a preliminary behavioral study on rats (+)-14b, and to a greater extent (+)-15b, promoted episodes of intense grooming, thus indicating that they act as central D1 agonists. The trans-2-amino-5-hydroxy-1-phenyl-2,3-dihydro-1H-indenes (+)-14b and (+)-15b represent selective D1 agonists lacking a catechol group, which should meet the prerequisites for a central nervous system penetration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
  • Animals
  • Benzazepines / pharmacology
  • Dopamine Agonists / pharmacology
  • Dopamine Antagonists / pharmacology
  • Grooming / drug effects
  • Indenes / chemical synthesis
  • Indenes / chemistry*
  • Ligands
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine / metabolism*
  • Stereoisomerism

Substances

  • Benzazepines
  • Dopamine Agonists
  • Dopamine Antagonists
  • Indenes
  • Ligands
  • Receptors, Dopamine
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine