Poster Number-23 - Cebranopadol, a Novel Potent Analgesic: Binding Affinity to Opioid Receptors and In Vitro Activity

Cebranopadol, a Novel Potent Analgesic: Binding Affinity to Opioid Receptors and In Vitro Activity

Purpose: Cebranopadol is a novel, highly potent, and centrally active opioid receptor agonist with high affinity for the μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors and lesser affinity for κ-opioid receptors and δ-opioid receptors.  This study investigated binding affinity of cebranopadol in human NOP, μ-opioid, κ-opioid, or δ-opioid receptor binding assays.

Methods:

Human μ-opioid, κ-opioid, δ-opioid, and NOP receptor binding assays were run in microtiter plates with preparations of cells transfected with the human μ-opioid receptor, the human δ-opioid receptor, the human κ-opioid receptor, or the human NOP receptor. After short mixing with radio-labeled ligands, the assays were incubated at room temperature for 60 to 90 minutes then centrifuged for 20 minutes. Half-maximal inhibitory concentration (IC₅₀) values reflecting 50% displacement of ligand-specific receptor binding were calculated by nonlinear regression analysis.

The agonistic activity of cebranopadol at the human NOP, μ-opioid, κ-opioid, or δ-opioid receptors was tested in [³⁵S]GTPgS binding assays with membranes from cells expressing the respective recombinant human receptors. The potency and efficacy of cebranopadol were compared with the functional activity of the selective NOP receptor agonist nociceptin/orphanin FQ, the μ-opioid receptor-selective enkephalin DAMGO, the κ-opioid receptor-selective agonist U69,593, and the δ-opioid receptor-selective agonist SNC 80.

Results:

Cebranopadol binds with high affinity to NOP and opioid receptors. Cebranopadol showed the most pronounced binding affinities at human NOP and μ-opioid receptors with subnanomolar inhibitory constants. In addition, cebranopadol showed a 3- to 4-fold weaker binding affinity in a human κ-opioid receptor binding assay, and an ∼20-to 26-fold lower affinity in a human δ-opioid receptor binding assay.

Cebranopadol showed full agonistic efficacy at the human μ-opioid and δ-opioid receptors, almost full efficacy at the human NOP receptor, and partial agonism at the human κ-opioid receptor.

Conclusion: Cebranopadol combines μ-opioid and NOP receptor agonism in a single molecule which may contribute functionally to its safety and analgesic activity. Ongoing clinical investigations will assist in determining the role of cebranopadol in pain therapy.

References: • Linz K, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014;349(3):535-548.
• Data on File, Tris Pharma, Inc. MP34
• Data on File, Tris Pharma, Inc. MP39
• Data on File, Tris Pharma, Inc. MP60