Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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Allosteric mGluR3 Modulators for the Treatment of Psychiatric Disorders Robert B. Kargbo* Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States hippocampus, neocortex, thalamus, and striatum, which are relevant to neuropsychiatric disorders. Glutamate binds mGluRs within the extracellular domain and transmits signals via the receptor protein to the intracellular signaling partners. Activation of the mGluR2/3 receptors in vivo inhibit presynaptic glutamate release and postsynaptic activation of potassium channels that control neuronal hyperpolarization. Invariably, mGluR2/3 receptors provide a negative feedback loop to keep glutamate transmission within the physiological range and prevent hyperexcitability from interfering with the normal brain function. The widespread expression of mGluRs make these receptors an attractive drug target, and validation of their therapeutic utility in neurological and psychiatric disorders such as Alzheimer’s disease, Parkinson’s disease, anxiety, depression, and schizophrenia. In addition, glutamatergic pathways have been shown to involve in a number of physiopathology of neuronal damages and injuries, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, AIDS-induced dementia, multiple sclerosis, stroke, hypoxia, traumatic brain injuries, and neuronal cell death caused by glutamate imbalanced. Overstimulation of the glutamate receptors has been shown to cause drug-induced neurotoxicity such as neurotoxic effects on striatal dopaminergic neurons seen with methamphetamine (METH). Orthosteric ligands targeting mGluR subtypes have been unsuccessful due to lack of subtype selectivity, unfavorable DMPK, and physiochemical properties. The first family of orthosteric modulators are highly polar and interact with the glutamate binding site of the mGluRs, which is localized in the extracellular N-terminal region of the receptor. Examples of orthosteric modulators are LY-367385 for group I mGluRs, LY379268 for group II mGluRs, and L-APA for group III mGluRs. However, allosteric mGluR modulators interact with the allosteric binding site and stabilize the receptor conformation resulting in equilibrium shift that increases or decreases the affinity or efficacy of an allosteric agonist. Significant efforts have been made in the discovery of allosteric ligands such as positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), and silent allosteric modulators (SAMs). The most advanced allosteric ligands targeting the mGluRs subtypes are for mGlu1, mGlu2, mGlu4, and mGlu5. Examples of allosteric modulators are MPEP for group I mGluRs, LY487379 for group II mGluRs, and VU0155041 for group III mGluRs. In schizophrenia, the underlying pathogenetic mechanism involves the glutamatergic hypothesis, which implicates hyperactivity of glutamatergic transmission in the limbic regions. Consequently, it has been postulated that agonists at mGluR2/3 receptors could decrease schizophrenic symptoms by reducing
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Important Compound Classes.
Title. Substituted Heterocyclic Compounds as Allosteric Modulators of Group II Metabotropic Glutamate Receptors Patent Application Number. WO 2018/206820 A1 Publication Date. November 15, 2018 Priority Application. EP 17170865.4 Priority Date. May 14, 2017 Inventors. Blayo, A.-L.; Catelain, T.; Dorange, I.; Genet, C.; Manteau, B.; Mayer, S.; Schann, S. Assignee Company. Mavalon Therapeutics Limited Disease Area. Neurologic and psychiatric disorders Biological Target. mGluR3 Summary. Glutamate is the most abundant neurotransmitter in the mammalian central nervous system (CNS) and exerts its excitatory effects via ionotropic or metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. In the CNS, L-glutamate (Glu), also known as excitatory amino-acid (EAA), is the main excitatory neurotransmitter, and gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter. There is a highly regulated balance of EAA and GABA in normal CNS functions, and the dysfunctions are implicated in various neurodegenerative or neurological disorders. Glutamate operates via two main classes of receptors; the ionotropic glutamate receptors (iGluRs), which are involved in opening of the cation channels in the cellular membrane of the neurons. The iGluRs are divided into three subtypes according to the depolarizing action of the agonists, and these are α-amino-3-hydroxy-5-methylisoxazole4-propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainic acid (KA). The other class consists of G-protein coupled receptors called metabotropic glutamate receptors (mGluRs). mGluRs belong to class C of G-protein coupled receptors (GPCRs) and are one of the best family of drug targets registered as therapeutic agents. There are eight mGluR subtypes that have been identified, and these are further classified into three groups based on transduction mechanism, structural homology, and pharmacology: group I includes mGlu1 and mGlu5, group II includes mGlu2 and mGlu3, and group III consists of mGlu4, mGlu6, mGlu7, and mGlu8. The mGluR2/mGluR3 have high sequence homology (∼70% at the amino acid level) and are localized throughout brain areas such as the amygdala, © XXXX American Chemical Society
Received: December 9, 2018
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DOI: 10.1021/acsmedchemlett.8b00619 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Biological Assay. Human mGluR3 positive allosteric modulator was evaluated using Ca2+ functional assay. Receptor activity was detected by changes in intracellular calcium measured using the fluorescent Ca2+ sensitive dye, Fluo4AM. Biological Data. The Table below shows dose response EC50 of mGluR3 positive allosteric modulator activities.
transmission at glutamatergic synapses, which is supported by a broad range of preclinical data. In preclinical studies using transgenic mice lacking the mGluR2 or mGluR3 receptor, it has been shown that antipsychotic effects are mediated by the mGluR2 and not the mGluR3 receptor. Activation of mGluR3 has been shown to cause neurotoxicity by inducing production of growth factor such as transformation growth factor β (TGF-β), exertion of neuroprotection in vitro in excitotoxicity models and nigrostriatal bundle (NSB), and a dopaminergic pathway protection of neurons in experimental animal model. Consequently, there is great need for novel mGluR2 PAMs that are selective for mGluR3 over mGluR2. Compound LY2140023, a selective mGluR2/3 receptor agonist, in a clinical phase II trial showed efficacy on schizophrenic subjects in providing positive symptoms without the side effects of weight gain, prolactin elevation, and extrapyramidal symptoms (EPS), which are associated with the antipsychotic medication olanzapine. However, LY2140023 failed to meet the primary end point in phase III clinical trial and was terminated. Examples of PAM that have reached clinical trials are AZD8529 and ADX71149 for treatment of schizophrenia. Compounds of this Patent Highlight exhibit highly potent positive allosteric modulatory activity on mGluR3 and have suitable pharmacokinetic properties as therapeutic agents. These mGluR3 modulators provide the means and methods for medical intervention in treating diseases or disorders associated with dysregulation of glutamatergic signaling and functions, including treatment of prophylaxis of acute and chronic neurologic and psychiatric disorders. Definitions. n = 0 to 4; A = aryl or heteroaryl; X and Y = N or C; Z = O, S, or N(-RZ); RZ = H, C1−C10 alkyl, C2−C10 alkenyl, C2−C10 alkynyl, aryl, and so forth. R2 and R3 = halogen, −CN, −OH, cycloalkyl; R4 = (C1−C10) alkyl, C2−C10 alkenyl, C2−C10 alkynyl. Key Structures.
Recent Review Articles. 1. Kumar, J.; Ismail, Z.; Hatta, N. H.; Baharuddin, N.; Hapidin, H.; Bee, Y.-T. G.; Yap, E.; Pakri Mohamed, R. Curr. Drug Targets 2018, 19, 907. 2. Suh, Y.; Chang, K.; Roche, K. W. Mol. Cell Neurosci. 2018, 91, 10. 3. Stansley, B. J.; Conn, P. J. Curr. Opin. Pharmacol. 2018, 38, 31. 4. Caprioli, D.; Justinova, Z.; Venniro, M.; Shaham, Y. Biol. Psychiatry 2018, 84, 180.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Robert B. Kargbo: 0000-0002-5539-6343 Notes
The author declares no competing financial interest.
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DOI: 10.1021/acsmedchemlett.8b00619 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
