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

Bart Vandormael; Danai-Dionysia Fourla; Alexandra Gramowski-Voss; Piotr Kosson; Dieter G Weiss; Olaf H-U Schröder; Andrzej Lipkowski; Zafiroula Georgoussi; Dirk Tourwé

doi:10.1021/jm200894e

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

J Med Chem. 2011 Nov 24;54(22):7848-59. doi: 10.1021/jm200894e. Epub 2011 Oct 20.

Authors

Bart Vandormael¹, Danai-Dionysia Fourla, Alexandra Gramowski-Voss, Piotr Kosson, Dieter G Weiss, Olaf H-U Schröder, Andrzej Lipkowski, Zafiroula Georgoussi, Dirk Tourwé

Affiliation

¹ Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.

PMID: 21978284
DOI: 10.1021/jm200894e

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Analgesics / chemical synthesis
Analgesics / chemistry
Analgesics / pharmacology
Animals
Anticonvulsants / chemical synthesis
Anticonvulsants / chemistry
Anticonvulsants / pharmacology
Benzazepines / chemical synthesis*
Benzazepines / chemistry
Benzazepines / pharmacology
Binding Sites
Cells, Cultured
Cerebral Cortex / drug effects
Cerebral Cortex / physiology
Cyclic AMP / biosynthesis
Humans
In Vitro Techniques
Mice
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Neural Networks, Computer
Neurons / drug effects
Neurons / metabolism
Oligopeptides / chemical synthesis*
Oligopeptides / chemistry
Oligopeptides / pharmacology
Phosphorylation
Radioligand Assay
Rats
Receptors, Opioid, delta / agonists*
Receptors, Opioid, mu / agonists*
Spinal Cord / drug effects
Spinal Cord / physiology
Structure-Activity Relationship

Substances

Analgesics
Anticonvulsants
Benzazepines
Dmt-NMe-Ala-Aba-Gly-NH2
Oligopeptides
Receptors, Opioid, delta
Receptors, Opioid, mu
Cyclic AMP
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3