Superpotent [Dmt1]Dermorphin Tetrapeptides Containing the 4-Aminotetrahydro-2-benzazepin-3-one Scaffold with Mixed μ/δ Opioid Receptor Agonistic Properties

Novel dermorphin tetrapeptides are described in which Tyr1 is replaced by Dmt1, where d-Ala2 and Gly4 are N-methylated, and where Phe3-Gly4 residue is substituted by the constrained Aba3-Gly4 peptidomimetic. Most of these peptidic ligands displayed binding affinities in the nanomolar range for both μ- and δ-opioid receptors but no detectable affinity for the κ-opioid receptor. Measurements of cAMP accumulation, phosphorylation of extracellular signal-regulated kinase (ERK1/2) in HEK293 cells stably expressing each of these receptors individually, and functional screening in primary neuronal cultures confirmed the potent agonistic properties of these peptides. The most potent ligand H-Dmt-NMe-d-Ala-Aba-Gly-NH2 (BVD03) displayed mixed μ/δ opioid agonist properties with picomolar functional potencies. Functional electrophysiological in vitro assays using primary cortical and spinal cord networks showed that this analogue possessed electrophysiological similarity toward gabapentin and sufentanil, which makes ...