A new metabotropic glutamate receptor agonist with in vivo anti-allodynic activity.
Bioorganic & medicinal chemistry 2010 Jun 25; In press
Stanley N NJ, Hutchinson M MR, Kvist T, Nielsen B, Mathiesen J JM, Bräuner-Osborne H, Avery T TD, Tiekink E ER, Pedersen D DS, Irvine R RJ, Abell A AD, Taylor D DK
Discipline of Chemistry, The University of Adelaide, Adelaide 5005, Australia; Discipline of Pharmacology, The University of Adelaide, Adelaide 5005, Australia.
As part of the vital search towards improved therapeutic agents for the treatment of neuropathic pain, the central nervous system glutamate receptors have become a major focus of research. Outlined herein are the syntheses of two new biologically active 3'-cycloalkyl-substituted carboxycyclopropylglycines, utilizing novel synthetic chemistry. The reaction between substituted 1,2-dioxines and an aminophosphonate furnished the cyclopropane core in a single step with all required stereochemistry of pendant groups. In vitro binding assays at metabotropic glutamate receptors revealed selective activity. In vivo testing in a rodent model of neuropathic pain indicated one amino acid significantly and dose-dependently decreased mechanical allodynia.