The influence of substitution at aromatic part of 1,2,3,4-tetrahydroisoquinoline on in vitro and in vivo 5-HT(1A)/5-HT(2A) receptor activities of its 1-adamantoyloaminoalkyl derivatives

Bioorg Med Chem. 2002 Jan;10(1):87-95. doi: 10.1016/s0968-0896(01)00236-x.

Abstract

Further structure-activity relationship (SAR) studies with the 1,2,3,4-tetrahydroisoquinoline (THIQ) class of 5-HT(1A) ligands led to the synthesis of new 1-adamantoyloaminoalkyl derivatives. The impact of substituent variations in the aromatic part of THIQ moiety on 5-HT(1A) and 5-HT(2A) receptor affinities, as well as in vivo functional properties of the investigated compounds were discussed. It was found that those modifications reduced the binding affinity for 5-HT(1A) receptors (in comparison with unsubstituted THIQ derivatives); however, the majority of new compounds still remained potent 5-HT(1A) ligands (K(i)=4.9-46 nM) and most of them showed features of partial agonists of postsynaptic 5-HT(1A) receptors. At the same time, their 5-HT(2A) receptor affinity was slightly increased (K(i)=40-1475 nM), which resulted in a loss of 5-HT(2A)/5-HT(1A) selectivity. 5-Br,8-OCH3 derivative-the most potent, mixed 5-HT(1A)/5-HT(2A) ligand-produced activation of presynaptic 5-HT(1A) receptors and showed properties of a 5-HT(2A) receptor antagonist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / chemistry*
  • Animals
  • In Vitro Techniques
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Rats
  • Rats, Wistar
  • Serotonin Antagonists / chemistry*
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / chemistry*
  • Serotonin Receptor Agonists / pharmacology*
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines*

Substances

  • Isoquinolines
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Tetrahydroisoquinolines
  • 1,2,3,4-tetrahydroisoquinoline
  • Adamantane