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

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; Craig William Lindsley

doi:10.2174/1570180815666181017131349

Challenges in the Discovery and Optimization of mGlu_2/4 Heterodimer Positive Allosteric Modulators

Lett Drug Des Discov. 2019 Dec;16(12):1387-1394. doi: 10.2174/1570180815666181017131349.

Authors

Mark Gallant Fulton^{1

2}, Matthew Thomas Loch^{1

3}, Caroline Anne Cuoco¹, Alice Lambert Rodriguez^{1

3}, Emily Days², Paige Newton Vinson², Krystian Andrezej Kozek^{2

3}, Charles David Weaver^{2

3}, Anna Louise Blobaum^{1

3}, Peter Jeffrey Conn^{1

2

3

4}, Colleen Marie Niswender^{1

2

3

4}, Craig William Lindsley^{1

2

3

5}

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
² Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
³ Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
⁴ Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁵ Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.

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 mGlu_2/4 heterodimer (EC₅₀ = 3.4 μM), but was peripherally restricted (rat K_p = 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 mGlu_2/4 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; mGlu2/4; metabotropic glutamate receptor; positive allosteric modulator; striatopallidal synapses; structure-activity relationship.

Abstract

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