Differentiation of opiate agonist and antagonist receptor binding by protein modifying reagents

OPIATE antagonists differ from opiates only by the replacement of the N-methyl substituent with an N-allyl, N-cylcopropylmethyl or related group. Antagonists can reverse the pharmacological effects of opiates and so are important in the treatment of opiate overdose. Drugs that combine agonist and antagonist activities have potential as relatively nonaddicting analgesics. Although their mutual pharmacological antagonism indicates that they act at the same binding site, pharmacological discrepancies have prompted speculation that agonist and antagonist binding sites are separate^1,2. Biochemical study of receptor binding^3-16 has shown that although opiate agonists and antagonists compete for the same receptor^3,4, there are differences in the way they interact with them^7,10. Physiological concentrations of sodium enhance the binding of ³H-antagonists but reduce that of ³H-agonists. Sodium diminishes the ability of pure agonists to inhibit binding of ³H-naloxone to the receptor, but has little influence on inhibitory effects of pure antagonists and intermediate effects on those of combination agonist-antagonist drugs. The molecular basis for these differences, however, is unclear. As a first step in this direction we now report that binding of opiate receptors is much more sensitive to degradation by protein reagents which are known to modify sulphydryl groups than is binding by opiate antagonists. This suggests that distinct binding sites exist for agonists and antagonists, although they may both be on the same receptor.