title: Superpotent [Dmt¹] dermorphin tetrapeptides containing the 4-aminotetrahydro-2-benzazepin-3-one scaffold with mixed μ/δ opioid receptor agonistic properties.
abstract: Novel dermorphin tetrapeptides are described in which Tyr(1) is replaced by Dmt(1), where d-Ala(2) and Gly(4) are N-methylated, and where Phe(3)-Gly(4) residue is substituted by the constrained Aba(3)-Gly(4) 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-NH(2) (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 it an interesting candidate for further study as an analgesic for neuropathic pain.
authors: Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
authors: Bart
authors: B
authors: Vandormael
authors: Danai-Dionysia
authors: DD
authors: Fourla
authors: Alexandra
authors: A
authors: Gramowski-Voss
authors: Piotr
authors: P
authors: Kosson
authors: Dieter G
authors: DG
authors: Weiss
authors: Olaf H-U
authors: OH
authors: Schröder
authors: Andrzej
authors: A
authors: Lipkowski
authors: Zafiroula
authors: Z
authors: Georgoussi
authors: Dirk
authors: D
authors: Tourwé
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016571:Neural Networks, Computer; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D000927:Anticonvulsants; D001552:Benzazepines; C569763:Dmt-NMe-Ala-Aba-Gly-NH2; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3