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Development of an N-Acyl Amino Acid That Selectively Inhibits the Glycine Transporter 2 To Produce Analgesia in a Rat Model of Chronic Pain.
Mostyn, Shannon N; Rawling, Tristan; Mohammadi, Sarasa; Shimmon, Susan; Frangos, Zachary J; Sarker, Subhodeep; Yousuf, Arsalan; Vetter, Irina; Ryan, Renae M; Christie, Macdonald J; Vandenberg, Robert J.
Afiliación
  • Mostyn SN; Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.
  • Rawling T; School of Mathematical and Physical Sciences, Faculty of Science , The University of Technology Sydney , Sydney , NSW 2007 , Australia.
  • Mohammadi S; Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.
  • Shimmon S; School of Mathematical and Physical Sciences, Faculty of Science , The University of Technology Sydney , Sydney , NSW 2007 , Australia.
  • Frangos ZJ; Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.
  • Sarker S; Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.
  • Yousuf A; Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.
  • Vetter I; Institute for Molecular Bioscience & School of Pharmacy , The University of Queensland , Brisbane , Qld 4072 , Australia.
  • Ryan RM; Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.
  • Christie MJ; Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.
  • Vandenberg RJ; Discipline of Pharmacology, School of Medical Sciences , University of Sydney , Sydney , NSW 2006 , Australia.
J Med Chem ; 62(5): 2466-2484, 2019 03 14.
Article en En | MEDLINE | ID: mdl-30714733
Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics, but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesizing lipid analogues with a range of amino acid head groups in both l- and d-configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. The potent inhibitor oleoyl-d-lysine (33) is also resistant to degradation in both human and rat plasma and liver microsomes, and is rapidly absorbed following an intraperitoneal injection to rats and readily crosses the blood-brain barrier. We demonstrate that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Transporte de Glicina en la Membrana Plasmática / Dolor Crónico / Aminoácidos / Analgésicos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Transporte de Glicina en la Membrana Plasmática / Dolor Crónico / Aminoácidos / Analgésicos Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos