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：

美国国家卫生研究院; 英国医学研究理事会;

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

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