Spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine-a structurally unique tetracyclic 5-HT2A receptor antagonist

Eur J Pharmacol. 2003 Dec 15;482(1-3):335-7. doi: 10.1016/j.ejphar.2003.09.059.

Abstract

Structural elaboration of phenylethylamine to spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine (SpAMDA) produces an agent with unexpectedly high affinity (K(i)=4 nM) at 5-HT(2A) receptors. It was shown that SpAMDA acts as a 5-HT(2A) receptor antagonist. The structure and molecular geometry of SpAMDA are not consistent with existing pharmacophore features, and a novel 5-HT(2A) antagonist pharmacophore model is proposed for the binding of aminomethyl-9,10-dihydroanthracene analogs. Thus, SpAMDA may be a structurally novel parent of a new class of 5-HT(2A) receptor antagonists that binds to the receptor in a unique fashion that is distinct from the binding topology of existing 5-HT(2A) receptor antagonists.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Anthracenes / chemistry*
  • Anthracenes / metabolism
  • Anthracenes / pharmacology
  • Mice
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism
  • Pyrrolidines / pharmacology
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Serotonin 5-HT2 Receptor Antagonists*
  • Serotonin Antagonists / chemistry*
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / pharmacology
  • Structure-Activity Relationship

Substances

  • Anthracenes
  • Pyrrolidines
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists