Development of Opioid Receptor Specific Antagonists

A new class of hexa-peptide opioid antagonists, termed acetalins, have been identified. Theyexhibit potent binding activity at mu specific opioid receptors, with approximately a 10-fold loweractivity at delta, and greater than 100-fold less binding activity at kappa-1 and kappa-2 receptors. Theyhave been found to be potent mu receptor antagonists in the guinea pig ileum assay, and relatively weakdelta antagonists in the mouse vas deferens assay. In order to increase the mu receptor specificity, thisstudy will involve the synthesis of 240 single position analogs of the most potent L- and D-amino acidacetalins (Ac-RFMWMR-NH2 and Ac-rfwink-NH2, respectively). The goal is to develop a highly muspecific receptor antagonist which is not broken down by proteolytic enzymes. The most specific muantagonists will be tested for their ability to antagonize the intestinal immobility caused by chronicmorphine treatment. The long term goal is to be able to block the deleterious effects of intestinalimmobility (constipation) in patients requiring long term morphine treatment.