Pharmacological characterization of the dermorphin analog [Dmt(1)]DALDA, ahighly potent and selective mu-opioid peptide

The dermorphin-derived peptide [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2), lab els mu -opioid receptors with high affinity and selectivity in receptor bin ding assays. In mouse, radiant heat tail-flick assay [Dmt(1)]DALDA produced profound spinal and supraspinal analgesia, being approximately 5000- and 1 00-fold more potent than morphine on a molar basis, respectively. When admi nistered systemically, [Dmt(1)]DALDA was over 200-fold more potent than mor phine. Pharmacologically, [Dmt(1)]DALDA was distinct from morphine. [Dmt(1) ]DALDA displayed no cross-tolerance to morphine in the model used and it re tained supraspinal analgesic activity in morphine-insensitive CXBK mice. Su praspinally, it also differed from morphine in its lack of sensitivity towa rds 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 interest ing and extraordinarily potent, systemically active peptide analgesic, rais ing the possibility of novel approaches in the design of clinically useful drugs. (C) 2001 Published by Elsevier Science B.V.