Superpotent [Dmt1]dermorphin tetrapeptides containing the 4-aminotetrahydro-2-benzazepin-3-one scaffold with mixed μ/δ opioid receptor agonistic properties

Article abstract of DOI:10.1021/jm200894e

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 - and -opioid receptors but no detectable affinity for the -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 / 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 it an interesting candidate for further study as an analgesic for neuropathic pain.