| Abstract: |
The dermorphin-derived peptide (Dmt1)DALDA (H-Dmt-D-Arg-Phe-Lys-NH2), also known as Super DALDA, labels mu-opioid receptors with high affinity and selectivity. The receptor mechanism of action of (Dmt1)DALDA appears distinct from that of morphine, as evidenced by antisense mapping studies where (Dmt1)DALDA is insensitive to MOR1 exon probes that reduce morphine analgesia. In addition (Dmt1)DALDA also displays a lack of cross-tolerance to morphine. In an attempt to further characterize and elucidate the mechanism of action of (Dmt1)DALDA, radiolabeled (Dmt1)DALDA has been synthesized. Binding studies using calf striatal membranes reveal that (3H)(Dmt1)DALDA labels mu-receptors with high affinity (KD=54pM). Competition studies using unlabeled (Dmt1)DALDA, DAMGO and morphine suggest that (3H)(Dmt1)DALDA is labelling a population of receptors that is inaccessible to both DAMGO and morphine. Although the profile of (Dmt1)DALDA fits that of a mu-opioid, it is clear that this peptide proceeds via a distinct receptor mechanism of action, therefore raising important questions regarding the mode of action of mu-ligands. |
