N-substituted 4beta-methyl-5-(3-hydroxyphenyl)-7alpha-amidomorphans are potent, selective kappa opioid receptor antagonists

J Med Chem. 2006 Mar 9;49(5):1781-91. doi: 10.1021/jm058264p.

Abstract

In a previous study, we identified (-)-N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(1-piperidinyl)propanamide (5a, KAA-1) as the first potent and selective kappa opioid receptor antagonist from the 5-(3-hydroxyphenyl)morphan class of opioids. In this study we report an improved synthesis of this class of compounds. The new synthetic method was used to prepare analogues 5b-r where the morphan N-substituent and 7alpha-amido group were varied. Most of the analogues showed sub-nanomolar potency for the kappa opioid receptor and were highly selective relative to the mu and delta opioid receptors. (-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-[2-(2-methylphenyl)ethyl]-2-azabicyclo[3.3.1]non-7-yl}propanamide (5n, MTHQ) is at least as potent and selective as nor-BNI as a kappa opioid receptor antagonist in the [35S]GTP-gamma-S in vitro functional test.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Humans
  • Radioligand Assay
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 3-(3,4-dihydroisoquinolin-2(1H)-yl)-N-(5-(3-hydroxyphenyl)-4-methyl-2-(2-(2-methylphenyl)ethyl)-2-azabicyclo(3.3.1)non-7-yl)propanamide
  • Bridged Bicyclo Compounds, Heterocyclic
  • Receptors, Opioid, kappa
  • Guanosine 5'-O-(3-Thiotriphosphate)