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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Letter Article

Challenges in the Discovery and Optimization of mGlu2/4 Heterodimer Positive Allosteric Modulators

Author(s): Mark Gallant Fulton, Matthew Thomas Loch, Caroline Anne Cuoco, Alice Lambert Rodriguez, Emily Days, Paige Newton Vinson, Krystian Andrezej Kozek, Charles David Weaver, Anna Louise Blobaum, Peter Jeffrey Conn, Colleen Marie Niswender* and Craig William Lindsley*

Volume 16, Issue 12, 2019

Page: [1387 - 1394] Pages: 8

DOI: 10.2174/1570180815666181017131349

open access plus

Abstract

Background: This article describes the challenges in the discovery and optimization of mGlu2/4 heterodimer Positive Allosteric Modulators (PAMs).

Methods: Initial forays based on VU0155041, a PAM of both the mGlu4 homodimer and the mGlu2/4 heterodimer, led to flat, intractable SAR that precluded advancement. Screening of a collection of 1,152 FDA approved drugs led to the discovery that febuxostat, an approved xanthine oxidase inhibitor, was a moderately potent PAM of the mGlu2/4 heterodimer (EC50 = 3.4 µM), but was peripherally restricted (rat Kp = 0.03). Optimization of this hit led to PAMs with improved potency (EC50s <800 nM) and improved CNS penetration (rat Kp >2, an ~100-fold increase).

Results: However, these new amide analogs of febuxostat proved to be either GIRK1/2 and GIRK1/4 activators (primary carboxamide congeners) or mGlu2 PAMs (secondary and tertiary amides) and not selective mGlu2/4 heterodimer PAMs.

Conclusion: These results required the team to develop a new screening cascade paradigm, and exemplified the challenges in developing allosteric ligands for heterodimeric receptors.

Keywords: Heterodimer, metabotropic glutamate receptor, mGlu2/4, positive allosteric modulator, structure-activity relationship, striatopallidal synapses.

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[1]
Matsubara, S.; Shiraishi, A.; Sakai, T.; Okuda, T.; Satake, H. Heterodimerization of the prostaglandin E2 receptor EP2 and the calcitonin receptor CTR. PLoS One, 2017, 12(11)e0187711
[http://dx.doi.org/10.1371/journal.pone.0187711] [PMID: 29095955]
[2]
Liu, J.; Zhang, Z.; Moreno-Delgado, D.; Dalton, J.A.; Rovira, X.; Trapero, A.; Goudet, C.; Llebaria, A.; Giraldo, J.; Yuan, Q.; Rondard, P.; Huang, S.; Liu, J.; Pin, J.P. Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer. eLife, 2017, 6e26985
[http://dx.doi.org/10.7554/eLife.26985] [PMID: 28829739]
[3]
Moreno Delgado, D.; Møller, T.C.; Ster, J.; Giraldo, J.; Maurel, D.; Rovira, X.; Scholler, P.; Zwier, J.M.; Perroy, J.; Durroux, T.; Trinquet, E.; Prezeau, L.; Rondard, P.; Pin, J.P. Pharmacological evidence for a metabotropic glutamate receptor heterodimer in neuronal cells. eLife, 2017, 6e25233
[http://dx.doi.org/10.7554/eLife.25233] [PMID: 28661401]
[4]
Carli, M.; Kolachalam, S.; Aringhieri, S.; Rossi, M.; Giovannini, L.; Maggio, R.; Scarselli, M. Dopamine D2 Receptors Dimers: How can we Pharmacologically Target Them? Curr. Neuropharmacol., 2018, 16(2), 222-230.
[http://dx.doi.org/10.2174/1570159X15666170518151127] [PMID: 28521704]
[5]
Lindsley, C.W.; Emmitte, K.A.; Hopkins, C.R.; Bridges, T.M.; Gregory, K.J.; Niswender, C.M.; Conn, P.J. Practical strategies and concepts in GPCR allosteric modulator discovery: Recent advances with metabotropic glutamate receptors. Chem. Rev., 2016, 116(11), 6707-6741.
[http://dx.doi.org/10.1021/acs.chemrev.5b00656] [PMID: 26882314]
[6]
Jacobson, K.A. New paradigms in GPCR drug discovery. Biochem. Pharmacol., 2015, 98(4), 541-555.
[http://dx.doi.org/10.1016/j.bcp.2015.08.085] [PMID: 26265138]
[7]
Yin, S.; Noetzel, M.J.; Johnson, K.A.; Zamorano, R.; Jalan-Sakrikar, N.; Gregory, K.J.; Conn, P.J.; Niswender, C.M. Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS. J. Neurosci., 2014, 34(1), 79-94.
[http://dx.doi.org/10.1523/JNEUROSCI.1129-13.2014] [PMID: 24381270]
[8]
Niswender, C.M.; Jones, C.K.; Lin, X.; Bubser, M.; Thompson Gray, A.; Blobaum, A.L.; Engers, D.W.; Rodriguez, A.L.; Loch, M.T.; Daniels, J.S.; Lindsley, C.W.; Hopkins, C.R.; Javitch, J.A.; Conn, P.J. Development and antiparkinsonian activity of VU0418506, a selective positive allosteric modulator of metabotropic glutamate receptor 4 homomers without activity at mGlu2/4 heteromers. ACS Chem. Neurosci., 2016, 7(9), 1201-1211.
[http://dx.doi.org/10.1021/acschemneuro.6b00036] [PMID: 27441572]
[9]
Engers, D.W.; Blobaum, A.L.; Gogliotti, R.D.; Cheung, Y-Y.; Salovich, J.M.; Garcia-Barrantes, P.M.; Daniels, J.S.; Morrison, R.; Jones, C.K.; Soars, M.G.; Zhuo, X.; Hurley, J.; Macor, J.E.; Bronson, J.J.; Conn, P.J.; Lindsley, C.W.; Niswender, C.M.; Hopkins, C.R. Discovery, synthesis and preclinical characterization of N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4). ACS Chem. Neurosci., 2016, 7(9), 1192-1200.
[http://dx.doi.org/10.1021/acschemneuro.6b00035] [PMID: 27075300]
[10]
Conn, P.J.; Lindsley, C.W.; Meiler, J.; Niswender, C.M. Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat. Rev. Drug Discov., 2014, 13(9), 692-708.
[http://dx.doi.org/10.1038/nrd4308] [PMID: 25176435]
[11]
Scholler, P.; Nevoltris, D.; de Bundel, D.; Bossi, S.; Moreno-Delgado, D.; Rovira, X.; Møller, T.C.; El Moustaine, D.; Mathieu, M.; Blanc, E.; McLean, H.; Dupuis, E.; Mathis, G.; Trinquet, E.; Daniel, H.; Valjent, E.; Baty, D.; Chames, P.; Rondard, P.; Pin, J.P. Allosteric nanobodies uncover a role of hippocampal mGlu2 receptor homodimers in contextual fear consolidation. Nat. Commun., 2017, 8(1), 1967.
[http://dx.doi.org/10.1038/s41467-017-01489-1] [PMID: 29213077]
[12]
Kammermeier, P.J. Functional and pharmacological characteristics of metabotropic glutamate receptors 2/4 heterodimers. Mol. Pharmacol., 2012, 82(3), 438-447.
[http://dx.doi.org/10.1124/mol.112.078501] [PMID: 22653971]
[13]
Sławińska, A.; Wierońska, J.M.; Stachowicz, K.; Pałucha-Poniewiera, A.; Uberti, M.A.; Bacolod, M.A.; Doller, D.; Pilc, A. Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu receptor. Neuropharmacology, 2013, 66, 225-235.
[http://dx.doi.org/10.1016/j.neuropharm.2012.05.001] [PMID: 22634361]
[14]
Ossowska, K.; Wardas, J.; Berghauzen-Maciejewska, K.; Głowacka, U.; Kuter, K.; Pilc, A.; Zorn, S.H.; Doller, D. Lu AF21934, a positive allosteric modulator of mGlu4 receptors, reduces the harmaline-induced hyperactivity but not tremor in rats. Neuropharmacology, 2014, 83, 28-35.
[http://dx.doi.org/10.1016/j.neuropharm.2014.03.018] [PMID: 24726309]
[15]
Rovira, X.; Malhaire, F.; Scholler, P.; Rodrigo, J.; Gonzalez-Bulnes, P.; Llebaria, A.; Pin, J.P.; Giraldo, J.; Goudet, C. Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors. FASEB J., 2015, 29(1), 116-130.
[http://dx.doi.org/10.1096/fj.14-257287] [PMID: 25342125]
[16]
Niswender, C.M.; Johnson, K.A.; Weaver, C.D.; Jones, C.K.; Xiang, Z.; Luo, Q.; Rodriguez, A.L.; Marlo, J.E.; de Paulis, T.; Thompson, A.D.; Days, E.L.; Nalywajko, T.; Austin, C.A.; Williams, M.B.; Ayala, J.E.; Williams, R.; Lindsley, C.W.; Conn, P.J. Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol. Pharmacol., 2008, 74(5), 1345-1358.
[http://dx.doi.org/10.1124/mol.108.049551] [PMID: 18664603]
[17]
Williams, R.; Johnson, K.A.; Gentry, P.R.; Niswender, C.M.; Weaver, C.D.; Conn, P.J.; Lindsley, C.W.; Hopkins, C.R. Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4). Bioorg. Med. Chem. Lett., 2009, 19(17), 4967-4970.
[http://dx.doi.org/10.1016/j.bmcl.2009.07.072] [PMID: 19640716]
[18]
Rovira, X.; Harrak, Y.; Trapero, A.; González-Bulnes, P.; Malhaire, F.; Pin, J.P.; Goudet, C.; Giraldo, J.; Llebaria, A. Exploring the active conformation of cyclohexane carboxylate positive allosteric modulators of the type 4 metabotropic glutamate receptor. ChemMedChem, 2014, 9(12), 2685-2698.
[http://dx.doi.org/10.1002/cmdc.201402190] [PMID: 25196639]
[19]
Maj, M.; Bruno, V.; Dragic, Z.; Yamamoto, R.; Battaglia, G.; Inderbitzin, W.; Stoehr, N.; Stein, T.; Gasparini, F.; Vranesic, I.; Kuhn, R.; Nicoletti, F.; Flor, P.J. (-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. Neuropharmacology, 2003, 45(7), 895-906.
[http://dx.doi.org/10.1016/S0028-3908(03)00271-5] [PMID: 14573382]
[20]
Engers, D.W.; Field, J.R.; Le, U.; Zhou, Y.; Bolinger, J.D.; Zamorano, R.; Blobaum, A.L.; Jones, C.K.; Jadhav, S.; Weaver, C.D.; Conn, P.J.; Lindsley, C.W.; Niswender, C.M.; Hopkins, C.R. Discovery, synthesis, and structure-activity relationship development of a series of N-(4-acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)) with CNS exposure in rats. J. Med. Chem., 2011, 54(4), 1106-1110.
[http://dx.doi.org/10.1021/jm101271s] [PMID: 21247167]
[21]
Becker, M.A.; Schumacher, H.R., Jr; Wortmann, R.L.; MacDonald, P.A.; Eustace, D.; Palo, W.A.; Streit, J.; Joseph-Ridge, N. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N. Engl. J. Med., 2005, 353(23), 2450-2461.
[http://dx.doi.org/10.1056/NEJMoa050373] [PMID: 16339094]
[22]
Kaufmann, K.; Romaine, I.; Days, E.; Pascual, C.; Malik, A.; Yang, L.; Zou, B.; Du, Y.; Sliwoski, G.; Morrison, R.D.; Denton, J.; Niswender, C.M.; Daniels, J.S.; Sulikowski, G.A.; Xie, X.S.; Lindsley, C.W.; Weaver, C.D. ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice. ACS Chem. Neurosci., 2013, 4(9), 1278-1286.
[http://dx.doi.org/10.1021/cn400062a] [PMID: 23730969]

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