VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy

被引：27

作者：

Nickols, Hilary Highfield ^{[1
,2
,3
]}

Yuh, Joannes P. ^{[1
]}

Gregory, Karen J. ^{[6
,7
]}

Morrison, Ryan D. ^{[2
,3
]}

Bates, Brittney S. ^{[2
,3
]}

Stauffer, Shaun R. ^{[4
,5
]}

Emmitte, Kyle A. ^{[2
,3
,4
,5
]}

Bubser, Michael ^{[2
,3
]}

Peng, Weimin ^{[2
,3
]}

Nedelcovych, Michael T. ^{[2
,3
]}

Thompson, Analisa ^{[2
,3
]}

Lv, Xiaohui ^{[2
,3
]}

Xiang, Zixiu ^{[2
,3
]}

Daniels, J. Scott ^{[2
,3
]}

Niswender, Colleen M. ^{[2
,3
]}

Lindsley, Craig W. ^{[2
,3
,4
,5
]}

Jones, Carrie K. ^{[2
,3
]}

Conn, P. Jeffrey ^{[2
,3
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Div Neuropathol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Dept Chem, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA

[6] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic, Australia

[7] Monash Univ, Dept Pharmacol, Parkville, Vic, Australia

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2016年 / 356卷 / 01期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

DOPA-INDUCED DYSKINESIA; SIGNAL-REGULATED KINASE; LONG-TERM DEPRESSION; MGLU5; RECEPTOR; PARKINSONS-DISEASE; RAT MODEL; 2-METHYL-6-(PHENYLETHYNYL)-PYRIDINE MPEP; GLUTAMATE-RECEPTOR-5; ANTAGONIST; GASTROESOPHAGEAL-REFLUX; FUNCTIONAL SELECTIVITY;

D O I：

10.1124/jpet.115.226597

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu(5)) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu(5) and inverse agonist activity of current mGlu(5) NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu(5) NAM, N, N-diethyl-5-((3-fluorophenyl) ethynyl) picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu(5) NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu(5) agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu(5) NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [H-3] inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu(5)-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu(5) occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu(5) NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu(5) and demonstrate an excellent CNS occupancy-efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models.

引用

页码：123 / 136

页数：14

共 50 条

[21] Administration of the metabotropic glutamate receptor subtype 5 allosteric modulator GET 73 with alcohol: A translational study in rats and humans
Haass-Koffler, Carolina L.
Goodyear, Kimberly
Loche, Antonella
Long, Victoria M.
Lobina, Carla
Tran, Harrison H.
Cacciaglia, Roberto
Swift, Robert M.
Colombo, Giancarlo
Leggio, Lorenzo
[J]. JOURNAL OF PSYCHOPHARMACOLOGY, 2018, 32 (02) : 163 - 173
[22] Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents
Engers, Julie L.
Rodriguez, Alice L.
Konkol, Leah C.
Morrison, Ryan D.
Thompson, Analisa D.
Byers, Frank W.
Blobaum, Anna L.
Chang, Sichen
Venable, Daryl F.
Loch, Matthew T.
Niswender, Colleen M.
Daniels, J. Scott
Jones, Carrie K.
Conn, P. Jeffrey
Lindsley, Craig W.
Emmitte, Kyle A.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (18) : 7485 - 7500
[23] Defining the Translational Pharmacology of Negative Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 in Rats and Nonhuman Primates
Shaffer, C.
Smith, D. L.
Cianfrogna, J.
Miller, E.
Grimwood, S.
Zasadny, K.
Currier, G.
McGinnis, D.
Seymour, P.
Trapa, P.
Smith, D. A.
Zaleska, M.
[J]. CURRENT NEUROPHARMACOLOGY, 2011, 9 : 59 - 59
[24] Negative allosteric modulators of metabotropic glutamate receptor subtype 5 protect against hepatic ischemia/reperfusion injury
Berardo, C.
Siciliano, V.
Di Pasqua, L. G.
Richelmi, P.
Nicoletti, F.
Vairetti, M.
Ferrigno, A.
[J]. JOURNAL OF HEPATOLOGY, 2018, 68 : S128 - S128
[25] Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5
Felts, Andrew S.
Bollinger, Katrina A.
Brassard, Christopher J.
Rodriguez, Alice L.
Morrison, Ryan D.
Daniels, J. Scott
Blobaum, Anna L.
Niswender, Colleen M.
Jones, Carrie K.
Conn, P. Jeffrey
Emmitte, Kyle A.
Lindsley, Craig W.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2019, 29 (01) : 47 - 50
[26] A double effect molecular switch leads to a novel potent negative allosteric modulator of metabotropic glutamate receptor 5
Gomez-Santacana, X.
Rovira, X.
Dalton, J. A.
Goudet, C.
Pin, J. P.
Gorostiza, P.
Giraldo, J.
Llebaria, A.
[J]. MEDCHEMCOMM, 2014, 5 (10) : 1548 - 1554
[27] Negative Allosteric Modulators of Metabotropic Glutamate Receptors Subtype 5 in Addiction: a Therapeutic Window
Mihov, Yoan
Hasler, Gregor
[J]. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 2016, 19 (07):
[28] ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization
Kalinichev, Mikhail
Rouillier, Melanie
Girard, Francoise
Royer-Urios, Isabelle
Bournique, Bruno
Finn, Terry
Charvin, Delphine
Campo, Brice
Le Poul, Emmanuel
Mutel, Vincent
Poli, Sonia
Neale, Stuart A.
Salt, Thomas E.
Luetjens, Robert
[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2013, 344 (03): : 624 - 636
[29] Discovery of positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGluR5)
Williams, DL
Lindsley, CW
[J]. CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (09) : 825 - 846
[30] Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias
Sengmany, K.
Gregory, K. J.
[J]. BRITISH JOURNAL OF PHARMACOLOGY, 2016, 173 (20) : 3001 - 3017

← 1 2 3 4 5 →