A series of fatty acid derivatives of naltrexamine and naltrexhydrazine were synthesized and evaluated for their persistent binding to opioid receptors. Members of this series were found to require greater than fíve washes for removal from mouse brain membranes when the fatty acyl chain was saturated. The presence of unsaturation in the fatty acyl groups enhanced the persistent binding. In this regard the persistent binding increased as a function of the number of double bonds, with the unsaturated congeners requiring greater than 10 washes for removal of the ligand from the membranes. The results of this study are consistent with the apparently important role of polyunsaturated fatty acids in the binding of ligands to opioid receptors.