(R)- and (S)-5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten- 8-ylamine. Stereoselective interactions with 5-HT1A receptors in the brain

J Med Chem. 1989 Oct;32(10):2311-8. doi: 10.1021/jm00130a015.

Abstract

The enantiomers of 5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten-8-++ +ylamine (3) have been synthesized and evaluated for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor activity by use of behavioral and biochemical tests in rats. In addition, the ability of the compounds to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The absolute configuration of the enantiomers of 3 was determined indirectly by X-ray diffraction of (+)-(8R,alpha R)-5,6,7,8-tetrahydro-1-methoxy-N-(alpha-phenethyl)-9H- benzocyclohepten-8-ylamine hydrochloride (9.HCl), a resolved synthetic precursor. The stereoselectivity of the interaction of 3 with 5-HT1A receptors was more pronounced than that of 8-hydroxy-2-(dipropylamino)tetralin (1; 8-OH-DPAT); only (R)-3 displayed 5-HT activity. However, (R)-3 was of lower potency than any of the enantiomers of 1. The enantiomer (S)-3, which was found to be inactive as a 5-HT-receptor agonist, appeared to be a weakly potent DA-receptor agonist whereas (R)-3 seemed to be devoid of dopaminergic activity. The conformational preferences of 3 were studied by use of NMR spectroscopy and molecular mechanics calculations. Preferred conformations of (R)-3 are similar in shape to those of the stereoselective 5-HT1A-receptor agonist (2R,3S)-8-hydroxy-3-methyl-2-(dipropylamino)tetralin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzocycloheptenes / chemical synthesis*
  • Benzocycloheptenes / pharmacology
  • Brain / drug effects
  • Brain / metabolism*
  • Dopamine / metabolism
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Motor Activity / drug effects
  • Rats
  • Rats, Inbred Strains
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism
  • Reserpine / pharmacology
  • Serotonin / metabolism
  • Serotonin Antagonists / chemical synthesis*
  • Stereoisomerism
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Benzocycloheptenes
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin
  • 6,7,8,9-tetrahydro-1-hydroxy-N,N-dipropyl-5H-benzocyclohepten-6-ylamine
  • Reserpine
  • Dopamine