• Article

Synthesis and pharmacological evaluation of highly potent [Dmt1]DALDA analogs

Structure variation of the highly potent and µ-selective, peripheral analgesic [D-Arg2,Lys4]dermorphin-(1–4)-amide (DALDA) [1] led to [Dmt1]DALDA, with 12-fold higher affinity than DALDA at µ-receptors and potency180-fold higher in the guinea pig ileum (GPI) assay. Receptor selectivity was maintained as well (Ki ?/ Ki µ = 14700 relative to 11400 for DALDA) [2]. [Dmt1]DALDA is a potent, systemically active peripheral opioid analgesic [3]. We had access to protected analogs of [Dmt1]DALDA which were utilized in a fragment condensation approach to the synthesis of gram-amounts of three antioxidants (including [Dmt1]DALDA) [4]. Encouraged by the recent report on the use of fluorescent analogs of [Dmt1]DALDA for confocal laser scanning microscopy (CLSM) and flow cytometry studies [5], these synthetic intermediates which may be blood-brain barrier(BBB)-permeant were examined for their bioactivity. Surprisingly, the protected analogs of [Dmt1]DALDA exhibited higher receptor selectivity compared to the parent peptide. The details of the synthetic approach and biological evaluation of these intermediates, having the masked side chain charges, is described.


Reddy, P., Lewin, A., & Schiller, P. W. (2009). Synthesis and pharmacological evaluation of highly potent [Dmt1]DALDA analogs. Advances in Experimental Medicine and Biology, 611, 473-474. DOI: 10.1007/978-0-387-73657-0_203