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

Abstract

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.