Syntheses and opioid receptor binding affinities of 8-amino-2,6-methano-3-benzazocines

J Med Chem. 2003 Feb 27;46(5):838-49. doi: 10.1021/jm020429w.

Abstract

8-Amino-2,6-methano-3-benzazocine derivatives have been made using Pd-catalyzed amination procedures, and their affinities for opioid receptors were assessed. The 8-amino group was hypothesized to be a replacement for the prototypic 8-OH substituent for 2,6-methano-3-benzazocines and related opiates. This OH group is generally required for binding yet is implicated in unfavorable pharmacokinetic characteristics such as low oral bioavailability and rapid clearance via O-glucuronidation. The core structures in which the 8-OH group was replaced were cyclazocine and its enantiomers, ethylketocyclazocine and its enantiomers, ketocyclazocine, and Mr2034. Many new analogues had high affinity for opioid receptors with several in the subnanomolar range. Highest affinity was seen in analogues with secondary 8-(hetero)arylamino appendages. Binding to opioid receptors was enantioselective with the (2R,6R,11R)-configuration preferred and high selectivity for mu and kappa over delta opioid receptors was observed within the series. Several derivatives were shown to have intrinsic opioid-receptor-mediated activity in [(35)S]GTPgammaS assays.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Azocines / chemical synthesis*
  • Azocines / chemistry
  • Azocines / pharmacology
  • Binding, Competitive
  • Brain / metabolism
  • CHO Cells
  • Cricetinae
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Ligands
  • Membranes
  • Radioligand Assay
  • Receptors, Opioid, delta / metabolism*
  • Receptors, Opioid, kappa / metabolism*
  • Receptors, Opioid, mu / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfur Radioisotopes

Substances

  • Azocines
  • Ligands
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Sulfur Radioisotopes
  • Guanosine 5'-O-(3-Thiotriphosphate)