Benzofuran Bioisosteres of Hallucinogenic Tryptamines

J Med Chem. 1992 May 29;35(11):2061-4. doi: 10.1021/jm00089a017.

Abstract

The benzofuran analogues of the hallucinogens 5-methoxy-N,N-dimethyltryptamine and 5-methoxy-alpha-methyltryptamine were synthesized and evaluated for affinity at the serotonin 5-HT2 and 5-HT1A receptors in rat brain homogenate, labeled with [125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ([125I]DOI) and [3H]-8-hydroxy-2-(N,N-di-n-propylamino)tetralin ([3H]-8-OH-DPAT), respectively. At the 5-HT2 receptor, the benzofurans had slightly decreased affinities, approximately one-third and one-sixth those of the indoles, for the primary amines and the tertiary amines, respectively. The benzofurans also had lower affinity at the 5-HT1A receptor, but decreased only about 20-30% from that of the indole isosteres. Thus, the 5-HT1A receptor is less discriminating with respect to preference for an indole versus a benzofuran, although all of the compounds did have higher affinities for the 5-HT2 receptor than for the 5-HT1A receptor. It is suggested that benzofurans may be useful in the design of serotonin receptor ligands.

Publication types

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

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Amphetamines / metabolism
  • Animals
  • Benzofurans / chemical synthesis*
  • Benzofurans / metabolism
  • Ethylamines / chemical synthesis*
  • Ethylamines / metabolism
  • Frontal Lobe / metabolism
  • Hallucinogens / chemical synthesis*
  • Hallucinogens / metabolism
  • Hippocampus / metabolism
  • Male
  • Molecular Structure
  • Rats
  • Rats, Inbred Strains
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists / chemical synthesis
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / metabolism
  • Tryptamines / chemical synthesis*
  • Tryptamines / metabolism

Substances

  • Amphetamines
  • Benzofurans
  • Ethylamines
  • Hallucinogens
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Tetrahydronaphthalenes
  • Tryptamines
  • N,N-dimethyl-2-(5-methoxybenzofuran-3-yl)ethanamine
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • 4-iodo-2,5-dimethoxyphenylisopropylamine