title: Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers.
abstract: Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson's disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu4 are coexpressed, whereas other compounds potentiate mGlu4 responses regardless of mGlu2 coexpression. We report here the discovery and characterization of VU0418506, a novel mGlu4 PAM with activity in rodent PD models. Using pharmacological approaches and Complemented Donor-Acceptor resonance energy transfer (CODA-RET) technology, we find that VU0418506 does not potentiate agonist-induced activity when mGlu2 and mGlu4 are heterodimerized, suggesting that the antiparkinsonian action of mGlu4 PAMs can be induced by compounds without activity at mGlu2/4 heteromers.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Division of Molecular Therapeutics, New York State Psychiatric Institute , New York, New York 10032, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Michael
authors.initials: M
authors.lastname: Bubser
authors.forename: Analisa
authors.initials: A
authors.lastname: Thompson Gray
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Loch
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.affiliation: Division of Molecular Therapeutics, New York State Psychiatric Institute , New York, New York 10032, United States.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology; D018698:Glutamic Acid / Q000494:pharmacology; D057809:HEK293 Cells; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D016627:Oxidopamine; D006220:Haloperidol; D001058:Apomorphine; C108823:metabotropic glutamate receptor 4
keywords: Allosteric modulator; Parkinson’s disease; metabotropic glutamate receptor