title: 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: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster , Corrensstraße 48, D-48149 Münster, Germany.
authors: Christian
authors: C
authors: Bourgeois
authors: Elena
authors: E
authors: Werfel
authors: Fabian
authors: F
authors: Galla
authors: Kirstin
authors: K
authors: Lehmkuhl
authors: Héctor
authors: H
authors: Torres-Gómez
authors: Dirk
authors: D
authors: Schepmann
authors: Babette
authors: B
authors: Kögel
authors: Thomas
authors: T
authors: Christoph
authors: Wolfgang
authors: W
authors: Straßburger
authors: Werner
authors: W
authors: Englberger
authors: Michael
authors: M
authors: Soeberdt
authors: Sabine
authors: S
authors: Hüwel
authors: Hans-Joachim
authors: HJ
authors: Galla
authors: Bernhard
authors: B
authors: Wünsch
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010147:Pain Measurement; D010539:Permeability; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists; D017480:Receptors, sigma / Q000819:agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000595016:2-(3,4-dichlorophenyl)-1-(8-(3-hydroxypyrrolidin-1-yl)perhydroquinoxalin-1-yl)ethan-1-one; D000701:Analgesics, Opioid; D011759:Pyrrolidines; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma