(3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu5: Discovery of a new tool compound with activity in the OSS mouse model of addiction

Craig W. Lindsley; Brittney S. Bates; Usha N. Menon; Satyawan B. Jadhav; Alexander S. Kane; Carrie K. Jones; Alice L. Rodriguez; P. Jeffrey Conn; Christopher M. Olsen; Danny G. Winder; Kyle A. Emmitte

doi:10.1021/cn100099n

(3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu₅: Discovery of a new tool compound with activity in the OSS mouse model of addiction

Craig W. Lindsley, Brittney S. Bates, Usha N. Menon, Satyawan B. Jadhav, Alexander S. Kane, Carrie K. Jones, Alice L. Rodriguez, P. Jeffrey Conn, Christopher M. Olsen, Danny G. Winder, Kyle A. Emmitte

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Glutamate is the major excitatory transmitter in the mammalian central nervous system (CNS), exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (group I: mGlu₁ and mGlu₅; group II: mGlu₂ and mGlu₃; group III: mGlu₄, mGlu₆, mGlu₇, and mGlu₈). Noncompetitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu₅ offer potential therapeutic applications in diseases such as pain, anxiety, gastresophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of structure-activity relationships (SAR) in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro- 5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu5 NAM in this novel assay.

Original language	English
Pages (from-to)	471-482
Number of pages	12
Journal	ACS Chemical Neuroscience
Volume	2
Issue number	8
DOIs	https://doi.org/10.1021/cn100099n
State	Published - 17 Aug 2011

Keywords

Addiction
MGlu
Negative allosteric modulator
Noncompetitive antagonist

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10.1021/cn100099n

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Lindsley, C. W., Bates, B. S., Menon, U. N., Jadhav, S. B., Kane, A. S., Jones, C. K., Rodriguez, A. L., Conn, P. J., Olsen, C. M., Winder, D. G., & Emmitte, K. A. (2011). (3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu₅: Discovery of a new tool compound with activity in the OSS mouse model of addiction. ACS Chemical Neuroscience, 2(8), 471-482. https://doi.org/10.1021/cn100099n

@article{4e9fbd5ddd714541a0bacc242c9a35ac,

title = "(3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu5: Discovery of a new tool compound with activity in the OSS mouse model of addiction",

abstract = "Glutamate is the major excitatory transmitter in the mammalian central nervous system (CNS), exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (group I: mGlu1 and mGlu5; group II: mGlu2 and mGlu3; group III: mGlu4, mGlu6, mGlu7, and mGlu8). Noncompetitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu5 offer potential therapeutic applications in diseases such as pain, anxiety, gastresophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of structure-activity relationships (SAR) in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro- 5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu5 NAM in this novel assay.",

keywords = "Addiction, MGlu, Negative allosteric modulator, Noncompetitive antagonist",

author = "Lindsley, {Craig W.} and Bates, {Brittney S.} and Menon, {Usha N.} and Jadhav, {Satyawan B.} and Kane, {Alexander S.} and Jones, {Carrie K.} and Rodriguez, {Alice L.} and Conn, {P. Jeffrey} and Olsen, {Christopher M.} and Winder, {Danny G.} and Emmitte, {Kyle A.}",

note = "Funding Information: C.W.L. receives funding from NIH, NIMH, NIDA, the Alzheimer's Association, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson&Johnson. C.K.J. receives funding from NIMH and Tennessee Valley Healthcare System (U.S. Department of Veteran's Affairs). P.J.C. receives funding from NIH, NIMH, NIDA, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson& Johnson. C.M.O. receives funding fromNIDA. D.G.W. receives funding from NIH, NIDA, NIAAA, and NIMH. K.A.E. receives funding from NIH. Funding Information: C.W.L. receives funding from NIH, NIMH, NIDA, the Alzheimer{\textquoteright}s Association, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson&Johnson. C.K.J. receives funding from NIMH and Tennessee Valley Healthcare System (U.S. Department of Veteran{\textquoteright}s Affairs). P.J.C. receives funding from NIH, NIMH, NIDA, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson&Johnson. C.M.O. receives funding from NIDA. D.G.W. receives funding from NIH, NIDA, NIAAA, and NIMH. K.A.E. receives funding from NIH. The authors thank NIDA (RO1 DA023947-01) and Seaside Therapeutics (VUMC33842) for their support of our programs in the development of noncompetitive antagonist of mGlu5. The authors also thank NIDA (K99 DA026994) for supporting the development and characterization of OSS. Publisher Copyright: {\textcopyright} 2011 American Chemical Society.",

year = "2011",

month = aug,

day = "17",

doi = "10.1021/cn100099n",

language = "English",

volume = "2",

pages = "471--482",

journal = "ACS Chemical Neuroscience",

issn = "1948-7193",

publisher = "American Chemical Society",

number = "8",

}

Lindsley, CW, Bates, BS, Menon, UN, Jadhav, SB, Kane, AS, Jones, CK, Rodriguez, AL, Conn, PJ, Olsen, CM, Winder, DG & Emmitte, KA 2011, '(3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu₅: Discovery of a new tool compound with activity in the OSS mouse model of addiction', ACS Chemical Neuroscience, vol. 2, no. 8, pp. 471-482. https://doi.org/10.1021/cn100099n

TY - JOUR

T1 - (3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu5

T2 - Discovery of a new tool compound with activity in the OSS mouse model of addiction

AU - Lindsley, Craig W.

AU - Bates, Brittney S.

AU - Menon, Usha N.

AU - Jadhav, Satyawan B.

AU - Kane, Alexander S.

AU - Jones, Carrie K.

AU - Rodriguez, Alice L.

AU - Conn, P. Jeffrey

AU - Olsen, Christopher M.

AU - Winder, Danny G.

AU - Emmitte, Kyle A.

N1 - Funding Information: C.W.L. receives funding from NIH, NIMH, NIDA, the Alzheimer's Association, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson&Johnson. C.K.J. receives funding from NIMH and Tennessee Valley Healthcare System (U.S. Department of Veteran's Affairs). P.J.C. receives funding from NIH, NIMH, NIDA, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson& Johnson. C.M.O. receives funding fromNIDA. D.G.W. receives funding from NIH, NIDA, NIAAA, and NIMH. K.A.E. receives funding from NIH. Funding Information: C.W.L. receives funding from NIH, NIMH, NIDA, the Alzheimer’s Association, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson&Johnson. C.K.J. receives funding from NIMH and Tennessee Valley Healthcare System (U.S. Department of Veteran’s Affairs). P.J.C. receives funding from NIH, NIMH, NIDA, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson&Johnson. C.M.O. receives funding from NIDA. D.G.W. receives funding from NIH, NIDA, NIAAA, and NIMH. K.A.E. receives funding from NIH. The authors thank NIDA (RO1 DA023947-01) and Seaside Therapeutics (VUMC33842) for their support of our programs in the development of noncompetitive antagonist of mGlu5. The authors also thank NIDA (K99 DA026994) for supporting the development and characterization of OSS. Publisher Copyright: © 2011 American Chemical Society.

PY - 2011/8/17

Y1 - 2011/8/17

N2 - Glutamate is the major excitatory transmitter in the mammalian central nervous system (CNS), exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (group I: mGlu1 and mGlu5; group II: mGlu2 and mGlu3; group III: mGlu4, mGlu6, mGlu7, and mGlu8). Noncompetitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu5 offer potential therapeutic applications in diseases such as pain, anxiety, gastresophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of structure-activity relationships (SAR) in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro- 5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu5 NAM in this novel assay.

AB - Glutamate is the major excitatory transmitter in the mammalian central nervous system (CNS), exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (group I: mGlu1 and mGlu5; group II: mGlu2 and mGlu3; group III: mGlu4, mGlu6, mGlu7, and mGlu8). Noncompetitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu5 offer potential therapeutic applications in diseases such as pain, anxiety, gastresophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of structure-activity relationships (SAR) in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro- 5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu5 NAM in this novel assay.

KW - Addiction

KW - MGlu

KW - Negative allosteric modulator

KW - Noncompetitive antagonist

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DO - 10.1021/cn100099n

M3 - Article

AN - SCOPUS:84971012261

VL - 2

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JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 8

ER -

(3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu₅: Discovery of a new tool compound with activity in the OSS mouse model of addiction

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Keywords

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