Derivatives of cis-2-amino-8-hydroxy-1-methyltetralin: mixed 5-HT1A-receptor agonists and dopamine D2-receptor antagonists

J Med Chem. 1995 Jan 6;38(1):150-60. doi: 10.1021/jm00001a020.

Abstract

(1S,2R)-8-Hydroxy-1-methyl-2-(dipropylamino)tetralin [(1S,2R)-3] has been previously characterized as a selective and potent but partial 5-HT1A-receptor agonist. In the present study, we have prepared derivatives of (1S,2R)- and (1R,2S)-3 in which various C8-substituents have been introduced. In addition, the enantiomers of the N-isopropyl-N-n-propylamino derivative of 3 were prepared. The new derivatives were tested in vivo by use of behavioral and biochemical tests in rats. In addition, the affinity of the compounds was studied by competition experiments with [3H]-8-OH-DPAT in rat brain tissue. The only new derivative which behaved like a selective 5-HT1A-receptor agonist was the C8-carboxamide derivative (1S,2R)-13. The other active derivatives, including (1S,2R)-3, have more complicated pharmacological profiles and may be best characterized as mixed 5-HT1A-receptor agonists/dopamine D2-receptor antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Body Temperature / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Dopamine Antagonists / chemical synthesis*
  • Dopamine Antagonists / metabolism
  • Dopamine Antagonists / pharmacology*
  • Dopamine D2 Receptor Antagonists*
  • Humans
  • Hydroxyindoleacetic Acid / metabolism
  • Male
  • Mice
  • Models, Molecular
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / metabolism
  • Serotonin Receptor Agonists / pharmacology*
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / chemical synthesis*
  • Tetrahydronaphthalenes / pharmacology*

Substances

  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Tetrahydronaphthalenes
  • Serotonin
  • Hydroxyindoleacetic Acid