title: Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications.
abstract: Extensive research into the functions of glutamate and glutamate receptors in the central nervous system (CNS) has shown an essential role of metabotropic glutamate (mGlu) receptors in normal brain functions, but also in neurological and psychiatric disorders. The precise functions of these receptors remain undefined, and progress toward understanding their functions has been hampered by the lack of selective ligands with appropriate pharmacokinetic properties. The Group I mGlu receptor, mGlu5, is well positioned to regulate and fine-tune neuronal excitability and synaptic transmission through its modulation of various signal transduction pathways and interactions with other transmitter systems. Therefore, the mGlu5 receptor may be an important therapeutic target for the treatment of disorders of the central nervous system. The discovery of MPEP 3, a non-competitive mGlu5 receptor antagonist, provided a potent, selective, systemically active tool compound for proof of concept studies in animal models of various disease states. These studies have led to greater understanding of possible therapeutic applications of mGlu5 receptor antagonists in recent years, suggesting their use in a number of disease states, including chronic pain, various psychiatric and neurological disorders, substance abuse and withdrawal, obesity and gastroesophageal reflux disease (GERD). Together, these findings have intensified efforts to find other non-competitive mGlu5 receptor antagonists and have led to the discovery of several second-generation compounds, a few of which are in preclinical evaluations. There have been several recent reviews on mGlu receptor. This article highlights recent efforts on the design, synthesis and development of novel, non-competitive mGlu5 receptor antagonists and studies to understand their in vitro mechanisms of action and in vivo pharmacological profiles. Emphasis is also given to recent advances in the potential therapeutic applications of non-competitive mGlu5 receptor antagonists.
authors.affiliation: NPS Pharmaceuticals Inc. 6850 Goreway Drive, Mississauga, ON, Canada, L4V 1V7. mslassi@npsp.com
authors.forename: Abdelmalik
authors.initials: A
authors.lastname: Slassi
authors.forename: Methvin
authors.initials: M
authors.lastname: Isaac
authors.forename: Louise
authors.initials: L
authors.lastname: Edwards
authors.forename: Alexander
authors.initials: A
authors.lastname: Minidis
authors.forename: David
authors.initials: D
authors.lastname: Wensbo
authors.forename: Jan
authors.initials: J
authors.lastname: Mattsson
authors.forename: Karolina
authors.initials: K
authors.lastname: Nilsson
authors.forename: Patrick
authors.initials: P
authors.lastname: Raboisson
authors.forename: Donald
authors.initials: D
authors.lastname: McLeod
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stormann
authors.forename: Lance G
authors.initials: LG
authors.lastname: Hammerland
authors.forename: Edwin
authors.initials: E
authors.lastname: Johnson
mesh_terms: D000818:Animals; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D011849:Radioactive Tracers; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate