Allylprodine analogs as receptor probes. Evidence that phenolic and nonphenolic ligands interact with different subsites on identical opioid receptors

Abstract

The meta-hydroxy analogs of allylprodine and related structures were synthesized and tested for narcotic agonist and antagonist activity on the electrically stimulated guinea pig ileum and by the hot-plate procedure in mice. meta-Hydroxyallylprodine is not an agonist or antagonist. Other phenolic congeners similarly have little or no activity. The fact that these results are in dramatic contrast with the structure-activity profile of morphine and closely related opiates has led to the proposal that the interaction of morphine and allylprodine (.alpha.-1) with the .mu. opioid receptor differs. This difference is postulated to arise from the recognition of the aromatic groups of morphine and .alpha.-1 by different aromatic-binding subsites of the receptor. These subsites may be identical with those which recognize the aromatic rings of the Tyr1 and Phe4 of the enkephalins and endorphins. A receptor model consistent with these results is proposed.