Novel (R)-2-amino-5-fluorotetralins: dopaminergic antagonists and inverse agonists

J Med Chem. 1996 Oct 25;39(22):4421-9. doi: 10.1021/jm960350p.

Abstract

A series of secondary and tertiary N-alkyl derivatives of (R)-2-amino-5-fluorotetralin have been prepared. The affinities of the compounds for [3H]raclopride-labeled cloned human dopamine (DA) D2 and D3 receptors as well as [3H]-8-OH-DPAT-labeled rat hippocampal 5-HT1A receptors were determined. In order to selectively determine affinities for the high-affinity agonist binding site at DA D2 receptors, the agonist [3H]quinpirole was used. The intrinsic activities of the compounds at DA D2 and D3 receptors were evaluated in a [35S]GTP gamma S binding assay. The novel compounds were characterized as dopaminergic antagonists or inverse agonists. The antagonist (R)-2-(butylpropylamino)-5-fluorotetralin (16) bound with high affinity (Ki = 4.4 nM) to the DA D3 receptor and was the most D3-selective compound (10-fold). (R)-2-[[4-(8-Aza-7, 9-dioxospiro[4.5]decan-8-yl)butyl]propylamino]-5-fluorote tralin (18) bound with very high affinity to both DA D3 and 5-HT1A receptors (Ki = 0.2 nM) and was also characterized as a dopaminergic antagonist. (R)-2-(Benzylpropylamino)-5-fluorotetralin (10) behaved as an inverse agonist at both DA D2 and D3 receptors. It decreased the basal [35S]GTP gamma S binding and potently inhibited the DA-stimulated [35S]GTP gamma S binding. It is apparent that the intrinsic activity of a 2-aminotetralin derivative may be modified by varying the N-alkyl substituents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / metabolism
  • Animals
  • Dopamine Agonists / chemistry*
  • Dopamine Agonists / metabolism
  • Dopamine Antagonists / chemistry*
  • Dopamine Antagonists / metabolism
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Humans
  • Male
  • Raclopride
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT1
  • Salicylamides / metabolism
  • Tetrahydronaphthalenes / chemistry*
  • Tetrahydronaphthalenes / metabolism

Substances

  • Dopamine Agonists
  • Dopamine Antagonists
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Salicylamides
  • Tetrahydronaphthalenes
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Raclopride
  • 8-Hydroxy-2-(di-n-propylamino)tetralin