Synthesis and Pharmacological Characterization of 2-(4-chloro-3-hydroxyphenyl)ethylamine and N,N-dialkyl Derivatives as Dopamine Receptor Ligands

J Med Chem. 1992 Nov 13;35(23):4408-14. doi: 10.1021/jm00101a018.

Abstract

2-(4-Chloro-3-hydroxyphenyl)ethylamine (4) and some derivatives were synthesized as dopamine (DA) receptor ligands. Amine 4 retains the dopaminergic pharmacophore 2-(3-hydroxyphenyl)-ethylamine, and the chlorine atom replaces the "para" hydroxyl group of DA. The derivatives 18a-e were obtained by introducing on the nitrogen of amine 4 the n-propyl and 2-phenylethyl or 3-phenylpropyl groups which can be accommodated by the D-2 receptor lipophilic sites 3C and pi 3, respectively. The affinity and selectivity of these compounds for D-1 and D-2 subtypes was determined in radioligand competition assays for the DA receptors of rat striatum membranes using [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) as radioligands. The amine 4 shows about 7-fold lower affinity than DA for both sites and is not able to discriminate between the two subtypes of DA receptors. The introduction of two n-propyl groups (18a) on the nitrogen atom reduces by one-half and doubles the affinity for D-1 and D-2 binding sites, respectively. The substitution of an n-propyl group with different alkylphenyl groups, to give compounds 18b-e, increases the affinity for the D-2 subtype from 19-fold to 36-fold. These compounds have the same affinity at the D-2 site as the DA agonist N-n-propyl-N-(2-phenylethyl)-2-(3-hydroxyphenyl)-ethylamine (2a) and are about 20 times more selective than DA for this binding site. In the assay for D-2 receptor mediated inhibition of adenylate cyclase activity, all the tested compounds behaved as D-2 agonists; N-n-propyl-N-[2(4-hydroxyphenyl)ethyl]- (18d) and N-n-propyl-N-(2-phenyl-ethyl)-2-(4-chloro-3-hydroxyphenyl)ethylamine (18b) were more effective than DA or 2a. On the other hand, all compounds were less effective than DA in stimulation of adenylate cyclase activity in rat striatal homogenates, a kind of effect which is mediated by the D-1 subtype of DA receptors. These results suggest that the nitrogen substitution enhances the affinity and selectivity for the D-2 receptor. In the adenylate cyclase assay, the compounds behave as potent D-2 agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Binding, Competitive
  • Brain / drug effects
  • Brain / enzymology
  • Dopamine Agents / chemical synthesis*
  • Dopamine Agents / chemistry
  • Dopamine Agents / pharmacology
  • Phenethylamines / chemical synthesis*
  • Phenethylamines / chemistry
  • Phenethylamines / pharmacology
  • Rats
  • Receptors, Dopamine / drug effects*
  • Structure-Activity Relationship
  • Tyramine / analogs & derivatives*
  • Tyramine / chemical synthesis
  • Tyramine / chemistry
  • Tyramine / pharmacology

Substances

  • Dopamine Agents
  • Phenethylamines
  • Receptors, Dopamine
  • 2-(4-chloro-3-hydroxyphenyl)ethylamine
  • Adenylyl Cyclases
  • Tyramine