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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics, Opioid / chemical synthesis
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Analgesics, Opioid / chemistry*
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Analgesics, Opioid / pharmacology
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Animals
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Binding, Competitive
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Blood-Brain Barrier / metabolism
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Brain / drug effects
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Brain / metabolism
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Endothelial Cells / metabolism
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Guinea Pigs
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HEK293 Cells
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Humans
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Liver / drug effects
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Liver / metabolism
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Male
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Mice
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Models, Molecular
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Pain Measurement
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Permeability
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Pyrrolidines / chemical synthesis
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Pyrrolidines / chemistry*
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Pyrrolidines / pharmacology
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Quinoxalines / chemical synthesis
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Quinoxalines / chemistry*
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Quinoxalines / pharmacology
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Radioligand Assay
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Rats
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Receptors, N-Methyl-D-Aspartate / agonists
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Receptors, Opioid, delta / agonists
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Receptors, Opioid, kappa / agonists*
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Receptors, Opioid, mu / agonists
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Receptors, sigma / agonists
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Stereoisomerism
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Structure-Activity Relationship
Substances
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2-(3,4-dichlorophenyl)-1-(8-(3-hydroxypyrrolidin-1-yl)perhydroquinoxalin-1-yl)ethan-1-one
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Analgesics, Opioid
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Pyrrolidines
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Quinoxalines
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Receptors, N-Methyl-D-Aspartate
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Receptors, Opioid, delta
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Receptors, Opioid, kappa
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Receptors, Opioid, mu
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Receptors, sigma