(1S)-1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: members of a novel class of very potent kappa opioid analgesics

J Med Chem. 1991 Aug;34(8):2624-33. doi: 10.1021/jm00112a042.

Abstract

The synthesis and structure-activity relationship (SAR) of a novel class of kappa opioid analgesics, 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4- tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines+ ++, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60 degrees was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of kappa receptor selectivity was a feature of this novel class of antinociceptive agents (mu/kappa ratio from 44 to 950 according to the nature of the basic moiety). SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 microM/kg sc) and kappa ligands (Ki(kappa) ca. 0.20 nM) identified so far.

Publication types

  • Comparative Study

MeSH terms

  • Analgesia
  • Analgesics / chemical synthesis*
  • Analgesics / metabolism
  • Animals
  • Chemical Phenomena
  • Chemistry
  • Isoquinolines / chemical synthesis*
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Mice
  • Molecular Conformation
  • Molecular Structure
  • Pain Measurement
  • Receptors, Opioid / metabolism*
  • Receptors, Opioid, kappa
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • X-Ray Diffraction

Substances

  • Analgesics
  • Isoquinolines
  • Receptors, Opioid
  • Receptors, Opioid, kappa
  • Thiophenes