title: Qualification of LSP1-2111 as a Brain Penetrant Group III Metabotropic Glutamate Receptor Orthosteric Agonist.
abstract: LSP1-2111 is a group III metabotropic glutamate receptor agonist with preference toward the mGlu4 receptor subtype. This compound has been extensively used as a tool to explore the pharmacology of mGlu4 receptor activation in preclinical animal behavioral models. However, the blood-brain barrier penetration of this amino acid derivative has never been studied. We report studies on the central nervous system (CNS) disposition of LSP1-2111 using quantitative microdialysis in rat. Significant unbound concentrations of the drug relative to its in vitro binding affinity and functional potency were established in extracellular fluid (ECF). These findings support the use of LSP1-2111 to study the CNS pharmacology of mGlu4 receptor activation through orthosteric agonist mechanisms.
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, United States.
authors.forename: Manuel
authors.initials: M
authors.lastname: Cajina
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, United States.
authors.forename: Megan
authors.initials: M
authors.lastname: Nattini
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, United States.
authors.forename: Dekun
authors.initials: D
authors.lastname: Song
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, United States.
authors.forename: Gennady
authors.initials: G
authors.lastname: Smagin
authors.affiliation: H. Lundbeck A/S, Ottiliavej 9, 2500 Copenhagen-Valby, Denmark.
authors.forename: Erling B
authors.initials: EB
authors.lastname: Jørgensen
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, United States.
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.affiliation: H. Lundbeck A/S, Ottiliavej 9, 2500 Copenhagen-Valby, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: H. Lundbeck A/S, Ottiliavej 9, 2500 Copenhagen-Valby, Denmark.
authors.forename: Dorthe Bach
authors.initials: DB
authors.lastname: Toft
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, United States.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Huang
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes , 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors.forename: Francine
authors.initials: F
authors.lastname: Acher
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, United States.
authors.forename: Dario
authors.initials: D
authors.lastname: Doller
keywords: G protein-coupled receptors; Metabotropic glutamate receptors; mGlu4 receptor; orthosteric agonist