Synthesis and pharmacological evaluation of 5-pyrrolidinylquinoxalines as a novel class of peripherally restricted κ-opioid receptor agonists.

Abstract

5-Pyrrolidinyl substituted perhydroquinoxalines were designed as conformationally restricted κ-opioid receptor agonists restricted to the periphery. The additional N atom of the quinoxaline system located outside the ethylenediamine κ pharmacophore allows the fine-tuning of the pharmacodynamic and pharmacokinetic properties. The perhydroquinoxalines were synthesized stereoselectively using the concept of late stage diversification of the central building blocks 14. In addition to high κ-opioid receptor affinity they demonstrate high selectivity over μ, δ, σ1, σ2, and NMDA receptors. In the [35S]GTPγS assay full agonism was observed. Because of their high polarity, the secondary amines 14a (log D7.4=0.26) and 14b (log D7.4=0.21) did not penetrate an artificial blood-brain barrier. 14b was able to inhibit the spontaneous pain reaction after rectal mustard oil application to mice (ED50=2.35 mg/kg). This analgesic effect is attributed to activation of peripherally located κ receptors, since 14b did not affect centrally mediated referred allodynia and hyperalgesia.

• Authors: Christian Bourgeois, Elena Werfel, Fabian Galla, Kirstin Lehmkuhl, Héctor Torres-Gómez, Dirk Schepmann, Babette Kögel, Thomas Christoph, Wolfgang Straßburger, Werner Englberger, Michael Soeberdt, Sabine Hüwel, Hans-Joachim Galla, Bernhard Wünsch
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 15 Pg. 6845-60 (Aug 14 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25062506 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(3,4-dichlorophenyl)-1-(8-(3-hydroxypyrrolidin-1-yl)perhydroquinoxalin-1-yl)ethan-1-one
• Analgesics, Opioid
• Pyrrolidines
• Quinoxalines
• Receptors, N-Methyl-D-Aspartate
• Receptors, Opioid, delta
• Receptors, Opioid, kappa
• Receptors, Opioid, mu
• Receptors, sigma

Topics

• Analgesics, Opioid (chemical synthesis, chemistry, pharmacology)
• Animals
• Binding, Competitive
• Blood-Brain Barrier (metabolism)
• Brain (drug effects, metabolism)
• Endothelial Cells (metabolism)
• Guinea Pigs
• HEK293 Cells
• Humans
• Liver (drug effects, metabolism)
• Male
• Mice
• Models, Molecular
• Pain Measurement
• Permeability
• Pyrrolidines (chemical synthesis, chemistry, pharmacology)
• Quinoxalines (chemical synthesis, chemistry, pharmacology)
• Radioligand Assay
• Rats
• Receptors, N-Methyl-D-Aspartate (agonists)
• Receptors, Opioid, delta (agonists)
• Receptors, Opioid, kappa (agonists)
• Receptors, Opioid, mu (agonists)
• Receptors, sigma (agonists)
• Stereoisomerism
• Structure-Activity Relationship