Synthesis and Structural Requirements of N-substituted Norapomorphines for Affinity and Activity at Dopamine D-1, D-2, and Agonist Receptor Sites in Rat Brain

J Med Chem. 1990 Jan;33(1):39-44. doi: 10.1021/jm00163a007.

Abstract

A series of N-substituted analogues of (R)-(-)-norapomorphine were synthesized to study the optimal structural requirements of the N-alkyl side chain to interact with D-1 and D-2 dopaminergic receptors as well as dopamine (DA) agonist binding sites. Evaluations included testing the affinity of these compounds for DA receptor sites in rat striatal tissue and assessing stereotypy as a behavioral index of dopaminergic activity. The electronic, steric, and lipophilic properties of the N-alkyl side chain were found to be related to affinity, D-2 selectivity, and dopaminergic activity. All 11 compounds evaluated had relatively low affinity at D-1 sites. Optimum D-2 and agonist-site affinity as well as agonist activity were exhibited by N-cyclopropylmethyl (7) greater than or equal to N-allyl (8) greater than or equal to N-propyl (4) or N-ethyl (3) substituted compounds. Branching of the N-alkyl side chain as in N-isopropyl (5) and N-isobutyl (6) markedly reduced the D-2 affinity and activity, presumably due to steric effects. The N-trifluoroethyl (10) and N-pentafluoropropyl (11) derivatives had low affinity for all their dopamine receptor sites and no agonistic activity; evidently, the highly electronegative F atoms decrease basicity of the N atom and therefore decrease the ability of the N atom to be cationic at physiological pH, a proposed requirement for high-affinity binding to DA receptors.

Publication types

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

MeSH terms

  • Animals
  • Apomorphine / analogs & derivatives*
  • Apomorphine / chemical synthesis
  • Apomorphine / metabolism
  • Apomorphine / pharmacology
  • Cell Membrane / metabolism
  • Chemical Phenomena
  • Chemistry
  • Corpus Striatum / metabolism
  • Male
  • Molecular Conformation
  • Molecular Structure
  • Rats
  • Rats, Inbred Strains
  • Receptors, Dopamine / drug effects
  • Receptors, Dopamine / metabolism*
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Stereotyped Behavior / drug effects

Substances

  • Receptors, Dopamine
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • norapomorphine
  • Apomorphine