From models to molecules: opioid receptor dimers, bivalent ligands, and selective opioid receptor probes.

Opiates have been the most widely investigated class of natural products.1 The two most prominent opiates, morphine and codeine, have had a long history of use and abuse. Numerous semisynthetic opiates have been synthesized in an effort to obtain analgesics that are free of tolerance, physical dependence, and addiction liability. The development of totally synthetic analgesics subsequently led to the development of diverse structural classes of ligands that mimic the actions of the opiates. Compounds with mixed agonist-antagonist activity during that period represented a new approach to reducing the abuse potential and some of the side effects associated with the classical opiates, and several of the analgesics in this group are presently employed clinically. In this presentation I will draw on selected examples from my research to illustrate how key conceptual models have led to the design of selective ligands, some of which are widely employed as pharmacologic tools for the investigation of opioid receptors. I will also illustrate how site-directed mutagenesis, when combined with the classical structure-activity relationship (SAR) approach, has led to the identification of amino acid residues on opioid receptors and groups on ligands that participate in molecular recognition.