TY - JOUR
T1 - Partial mGlu 5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects
AU - Gould, Robert W.
AU - Amato, Russell J.
AU - Bubser, Michael
AU - Joffe, Max E.
AU - Nedelcovych, Michael T.
AU - Thompson, Analisa D.
AU - Nickols, Hilary H.
AU - Yuh, Johannes P.
AU - Zhan, Xiaoyan
AU - Felts, Andrew S.
AU - Rodriguez, Alice L.
AU - Morrison, Ryan D.
AU - Byers, Frank W.
AU - Rook, Jerri M.
AU - Daniels, John S.
AU - Niswender, Colleen M.
AU - Conn, P. Jeffrey
AU - Emmitte, Kyle A.
AU - Lindsley, Craig W.
AU - Jones, Carrie K.
N1 - Funding Information:
The authors thank Alyssa Lokits, Grant Muller, Jermaine Wilson, Weimin Peng, and Daryl Venable for their expert technical assistance. Studies were performed in part through the use of the Rodent Neurobehavior Core at the Vanderbilt University Medical Center. This work was funded in part by NIH DA023947 (CWL), MH97056 (PJC), Seaside Therapeutics (VUMC33842), as well as the Barrus Foundation (CKJ) and a PhRMA Foundation postdoctoral fellowship grant in Pharmacology and Toxicology (RWG).
Funding Information:
RWG’s work has been funded by the NIH and the Pharmaceutical Research and Manufacturers of America Foundation. RJA’s work has been funded by the NIH. MB’s work has been funded by the NIH, Bristol-Myers Squibb, Johnson and Johnson, AstraZeneca, and Autism Speaks. MEJ’s work has been funded by NIH. MTN has been funded by NIH. ADT’s work has been funded by the NIH, Bristol-Myers Squibb, Johnson and Johnson, AstraZeneca, and Autism Speaks. HHN’s work has been funded by NIH. JPY’s work has been funded by NIH. XZ’s work has been funded by the NIH, Bristol-Myers Squibb, and AstraZeneca. ASF’s work has been funded by NIH and received compensation from Seaside Therapeutics. ALR’s work has been funded by the NIH and collaborative research agreements with Seaside Therapeutics. She is an inventor on patents that protect different classes of mGlu5allosteric modulators. RDM’s work has been funded by NIH. FWB’s work has been funded by NIH. JMR’s work has been funded by NIH, Alzheimer’s Drug Discovery Foundation, and The Alzheimer’s Disease Drug Discovery Foundation. JSD’s work has been funded in part by the NIH and the Molecular Libraries Probe Production Centers Network. He has received compensation from Johnson and Johnson, Bristol-Myers Squibb, Seaside Therapeutics, and as a member of the scientific advisory board of the Sigma-Aldrich company and through consulting for Agios Pharmaceuticals Company and the Michael J. Fox Foundation. He is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. CMN’s work has been funded by the NIH, rettsyndrome.org and Autism Speaks. She has received licensing royalties from Johnson and Johnson, Bristol-Myers Squibb, AstraZeneca and Seaside Therapeutics, and is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. PJC has been funded by NIH, Johnson and Johnson, AstraZeneca, Bristol-Myers Squibb, Michael J. Fox Foundation, and Seaside Therapeutics. He has consulted over the past 3 years for Pfizer, Cambridge, and Millipore Corporation, and received compensation. Over the past 3 years, he has served on the Scientific Advisory Boards and received compensation from Seaside Therapeutics, Michael J. Fox Foundation, Stanley Center for Psychiatric Research Broad Institute (MIT/Harvard), Karuna Pharmaceuticals, Lieber Institute for Brain Development, Johns Hopkins University, Clinical Mechanism and Proof of Concept Consortium, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder. He is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. KAE’s work has been funded by the NIH and collaborative research agreements with Seaside Therapeutics. He is an inventor on patents that protect different classes of mGlu5 NAMs. CWL’s work has been funded by the NIH, Bristol-Myers Squibb, AstraZeneca, Michael J. Fox Foundation, as well as Seaside Therapeutics. He has consulted for Abbott, AbbVie and received compensation. He is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. CKJ received research support from Bristol-Myers Squibb, Johnson and Johnson, and AstraZeneca. CKJ also received funding through the Michael J. Fox Foundation, the Barrus Foundation, Autism Speaks, and the NIH. She is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. The authors RWG, RJA, HHN, MEJ, MTN, JPY, RDM, and FWB declare no competing financial interests.
Funding Information:
RWG''s work has been funded by the NIH and the Pharmaceutical Research and Manufacturers of America Foundation. RJA''s work has been funded by the NIH. MB''s work has been funded by the NIH, Bristol-Myers Squibb, Johnson and Johnson, AstraZeneca, and Autism Speaks. MEJ''s work has been funded by NIH. MTN has been funded by NIH. ADT''s work has been funded by the NIH, Bristol- Myers Squibb, Johnson and Johnson, AstraZeneca, and Autism Speaks. HHN''s work has been funded by NIH. JPY''s work has been funded by NIH. XZ''s work has been funded by the NIH, Bristol-Myers Squibb, and AstraZeneca. ASF''s work has been funded by NIH and received compensation from Seaside Therapeutics. ALR''s work has been funded by the NIH and collaborative research agreements with Seaside Therapeutics. She is an inventor on patents that protect different classes of mGlu
Publisher Copyright:
© 2016 American College of Neuropsychopharmacology.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu 5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu 5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu 5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu 5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu 5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-Administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant-and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-To-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu 5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu 5 NAMs, but with a broader therapeutic index.
AB - Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu 5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu 5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu 5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu 5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu 5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-Administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant-and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-To-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu 5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu 5 NAMs, but with a broader therapeutic index.
UR - http://www.scopus.com/inward/record.url?scp=84957594483&partnerID=8YFLogxK
U2 - 10.1038/npp.2015.265
DO - 10.1038/npp.2015.265
M3 - Article
C2 - 26315507
AN - SCOPUS:84957594483
VL - 41
SP - 1166
EP - 1178
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 4
ER -