Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist for the treatment of gastrointestinal motility disorders

J Med Chem. 1994 Jul 22;37(15):2262-5. doi: 10.1021/jm00041a003.


Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (Ki = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (> 200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.

MeSH terms

  • Animals
  • Diarrhea / chemically induced
  • Gastrointestinal Motility / drug effects*
  • Guinea Pigs
  • In Vitro Techniques
  • Intestinal Diseases / drug therapy*
  • Male
  • Mice
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Radioligand Assay
  • Receptors, Opioid, mu / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Piperidines
  • Receptors, Opioid, mu