Synthesis and Dopamine Receptor Affinities of 2-(4-fluoro-3- Hydroxyphenyl)ethylamine and N-substituted Derivatives

J Med Chem. 1990 Sep;33(9):2408-12. doi: 10.1021/jm00171a014.

Abstract

The synthesis of 2-(4-fluoro-3-hydroxyphenyl)ethylamine (26) and of some N,N-dialkyl derivatives (27-30) starting from 4-fluoro-3-hydroxytoluene and their in vitro binding affinities for dopamine (DA) receptor are reported. The amine 26 can be regarded as a molecular modification of DA in which the para hydroxyl group is replaced by fluorine. The new compounds 26-30 were evaluated for their affinity at D-1 and D-2 DA receptor subtypes by displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective). The amine 26 had about 2-fold less affinity for D-1 and D-2 binding sites than DA. The substitution of the amino group with ethyl, n-propyl, and 2-phenylethyl groups decreased the affinity for D-1 binding sites but greatly enhanced the effectiveness on D-2 binding sites. The N-ethyl- (28) and N-n-propyl-N-(2-phenylethyl)-2-(4-fluoro-3- hydroxyphenyl)ethylamine (30) were the most potent members of the series with high selectivity for D-2 binding sites. A similar effect was observed with isomeric N-n-propyl-N-(2-phenylethyl)-2-(3-fluoro-4-hydroxyphenyl)ethylamine (31) which was approximately 65 times more selective for D-2 sites vs D-1 sites. The introduction of a 2-phenylethyl group on the nitrogen atom induce the highest effect, perhaps as a consequence of an increased liposolubility or of binding to a complementary lipophilic site on the receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzazepines / metabolism
  • Chemical Phenomena
  • Chemistry
  • Dopamine Agents / chemical synthesis*
  • Dopamine Agents / pharmacology
  • Dopamine Antagonists
  • Phenethylamines / chemical synthesis*
  • Phenethylamines / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptors, Dopamine / drug effects
  • Structure-Activity Relationship

Substances

  • Benzazepines
  • Dopamine Agents
  • Dopamine Antagonists
  • Phenethylamines
  • Receptors, Dopamine