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Letters in Drug Design & Discovery


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

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


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.

Graphical Abstract
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