4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines: A Novel Class of Compounds With Central Dopamine Agonist Properties

J Med Chem. 1990 Jan;33(1):311-7. doi: 10.1021/jm00163a051.

Abstract

The design, synthesis, and pharmacological properties of a novel type of 4-(1,2,5,6-tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamine with dopaminergic properties are described. In particular, 4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine (4c, PD 118440) and its allyl analogue (4i, PD 120697) have been identified as orally active dopamine (DA) agonists with pronounced central nervous system effects in tests that include [3H]-haloperidol and [3H]-N-propylnorapomorphine binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. The DA autoreceptor selectivity of these heterocyclic analogues of 3-(1-propyl-3-piperidinyl)phenol (3-PPP) was also evaluated. In this series, DA agonist activity was found to be highly dependent on the size of the N-alkyl substituent, the saturation level of the six-membered ring, and the mode of attachment of the 2-aminothiazole ring.

MeSH terms

  • Animals
  • Apomorphine / analogs & derivatives
  • Apomorphine / metabolism
  • Chemical Phenomena
  • Chemistry
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology
  • Dihydroxyphenylalanine / biosynthesis
  • Dopamine / biosynthesis
  • Dopamine Agents*
  • Haloperidol / metabolism
  • Male
  • Molecular Conformation
  • Molecular Structure
  • Motor Activity / drug effects
  • Neurons / physiology
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology*
  • Rats
  • Receptors, Dopamine / drug effects
  • Receptors, Dopamine / physiology
  • Receptors, Dopamine D2
  • Structure-Activity Relationship
  • Substantia Nigra / physiology
  • Thermodynamics
  • Thiazoles / chemical synthesis
  • Thiazoles / pharmacology*

Substances

  • Dopamine Agents
  • Pyridines
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Thiazoles
  • PD 118440
  • PD 120697
  • N-n-propylnorapomorphine
  • Dihydroxyphenylalanine
  • Haloperidol
  • Apomorphine
  • Dopamine