Pharmacological characterization of the dermorphin analog [Dmt 1]DALDA, a highly potent and selective μ-opioid peptide

Abstract

The dermorphin-derived peptide [Dmt 1]DALDA (H-Dmt- d-Arg-Phe-Lys-NH 2), labels μ-opioid receptors with high affinity and selectivity in receptor binding assays. In mouse, radiant heat tail-flick assay [Dmt 1]DALDA produced profound spinal and supraspinal analgesia, being approximately 5000- and 100-fold more potent than morphine on a molar basis, respectively. When administered systemically, [Dmt 1]DALDA was over 200-fold more potent than morphine. Pharmacologically, [Dmt 1]DALDA was distinct from morphine. [Dmt 1]DALDA displayed no cross-tolerance to morphine in the model used and it retained supraspinal analgesic activity in morphine-insensitive CXBK mice. Supraspinally, it also differed from morphine in its lack of sensitivity towards naloxonazine. Finally, in antisense mapping studies, [Dmt 1]DALDA was insensitive to MOR-1 exon probes that reduced morphine analgesia, implying a distinct receptor mechanism of action. Thus, [Dmt 1]DALDA is an interesting and extraordinarily potent, systemically active peptide analgesic, raising the possibility of novel approaches in the design of clinically useful drugs.