Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology.

Sengmany, Kathy; Hellyer, Shane D; Albold, Sabine; Wang, Taide; Conn, P Jeffrey; May, Lauren T; Christopoulos, Arthur; Leach, Katie; Gregory, Karen J

Sengmany, Kathy; Hellyer, Shane D; Albold, Sabine; Wang, Taide; Conn, P Jeffrey; May, Lauren T; Christopoulos, Arthur; Leach, Katie; Gregory, Karen J.

Afiliación

Sengmany K; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, Parkville, VIC, Australia.
Hellyer SD; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, Parkville, VIC, Australia.
Albold S; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, Parkville, VIC, Australia.
Wang T; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, Parkville, VIC, Australia.
Conn PJ; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
May LT; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, Parkville, VIC, Australia.
Christopoulos A; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, Parkville, VIC, Australia.
Leach K; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, Parkville, VIC, Australia.
Gregory KJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, Parkville, VIC, Australia. Electronic address: karen.gregory@monash.edu.

Neuropharmacology ; 149: 83-96, 2019 05 01.

Article en En | MEDLINE | ID: mdl-30763654

RESUMEN

Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5) have been proposed as potential therapies for various CNS disorders. These ligands bind to sites distinct from the orthosteric (or endogenous) ligand, often with improved subtype selectivity and spatio-temporal control over receptor responses. We recently revealed that mGlu5 allosteric agonists and positive allosteric modulators exhibit biased agonism and/or modulation. To establish whether negative allosteric modulators (NAMs) engender similar bias, we rigorously characterized the pharmacology of eight diverse mGlu5 NAMs. Radioligand inhibition binding studies revealed novel modes of interaction with mGlu5 for select NAMs, with biphasic or incomplete inhibition of the radiolabeled NAM, [3H]methoxy-PEPy. We assessed mGlu5-mediated intracellular Ca2+ (iCa2+) mobilization and inositol phosphate (IP1) accumulation in HEK293A cells stably expressing low levels of mGlu5 (HEK293A-rat mGlu5-low) and mouse embryonic cortical neurons. The apparent affinity of acetylenic NAMs, MPEP, MTEP and dipraglurant, was dependent on the signaling pathway measured, agonist used, and cell type (HEK293A-rat mGlu5-low versus mouse cortical neurons). In contrast, the acetylenic partial NAM, M-5MPEP, and structurally distinct NAMs (VU0366248, VU0366058, fenobam), had similar affinity estimates irrespective of the assay or cellular background. Biased modulation was evident for VU0366248 in mouse cortical neurons where it was a NAM for DHPG-mediated iCa2+ mobilization, but neutral with DHPG in IP1 accumulation assays. Overall, this study highlights the inherent complexity in mGlu5 NAM pharmacology that we hypothesize may influence interpretation when translating into preclinical models and beyond in the design and development of novel therapeutics for neuropsychiatric and neurological disorders.

Asunto(s)

Regulación Alostérica/efectos de los fármacos; Ligandos; Receptor del Glutamato Metabotropico 5/metabolismo; Animales; Calcio/metabolismo; Sistema Nervioso Central; Femenino; Células HEK293; Humanos; Fosfatos de Inositol/metabolismo; Cinética; Ratones; Embarazo; Cultivo Primario de Células; Ratas

Palabras clave

(PubChem CID: 108001); (PubChem CID: 16036762); (PubChem CID: 162834); (PubChem CID: 3025961); (PubChem CID: 44557636); (PubChem CID: 57328392); (PubChem CID: 9794218); (l-glutamic acid PubChem CID: 33032); Biased modulation; DHPG; Glutamate; Kinetics; M-5MPEP; MPEP; MTEP; Metabotropic glutamate receptor 5; Negative allosteric modulator; VU0366058; dipraglurant; fenobam

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación Alostérica / Receptor del Glutamato Metabotropico 5 / Ligandos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Pregnancy Idioma: En Revista: Neuropharmacology Año: 2019 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google