Based on an analysis of results taken from site-directed mutagenesis studies performed on opioid receptors, a role for the extracellular loops in conferring opioid subtype selectivity is proposed. It is suggested that the extracellular loop regions (which represent the region of highest sequence variability among opioid subtypes) interact with opioid ligands in a primarily non-specific fashion. Although these interactions are non-specific, they appear to play a discriminatory role in ligand binding and, in certain cases, prevent particular ligands from binding among receptor subtypes. We propose that selectivity may be imparted through a mechanism of exclusion, rather than specific pharmacophore recognition within the extracellular loops and N-terminal domain. This hypothesis is supported by a careful analysis of the binding profiles of several selective and non-selective ligands to a variety of chimeric mutants. These results, when combined with results taken from single-point mutation experiments point to the existence of a high affinity binding pocket within the transmembrane region which may be common among the opioid subtypes.
