title: Partial mGlu₅ Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects.
abstract: 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 (mGlu5) 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 mGlu5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu5 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 mGlu5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu5 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 mGlu5 NAMs in these assays corresponded with increasing in vivo mGlu5 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 mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu5 NAMs, but with a broader therapeutic index.
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Robert W
authors: RW
authors: Gould
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Russell J
authors: RJ
authors: Amato
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Michael
authors: M
authors: Bubser
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Max E
authors: ME
authors: Joffe
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Michael T
authors: MT
authors: Nedelcovych
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Analisa D
authors: AD
authors: Thompson
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pathology, Microbiology and Immunology, Division of Neuropathology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Hilary H
authors: HH
authors: Nickols
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Johannes P
authors: JP
authors: Yuh
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Xiaoyan
authors: X
authors: Zhan
authors: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Andrew S
authors: AS
authors: Felts
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Alice L
authors: AL
authors: Rodriguez
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Ryan D
authors: RD
authors: Morrison
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Frank W
authors: FW
authors: Byers
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Jerri M
authors: JM
authors: Rook
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: John S
authors: JS
authors: Daniels
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Colleen M
authors: CM
authors: Niswender
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: P Jeffrey
authors: PJ
authors: Conn
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Kyle A
authors: KA
authors: Emmitte
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Craig W
authors: CW
authors: Lindsley
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors: Carrie K
authors: CK
authors: Jones
mesh_terms: D000480:Alkynes / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage; D000928:Antidepressive Agents / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage*; D003214:Conditioning, Classical / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*; D012646:Self Administration; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000611988:2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine; C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D000480:Alkynes; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles; D003042:Cocaine; D010622:Phencyclidine