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

(E-pub Ahead of Print)

Author(s): Mark G. Fulton , Matthew T. Loch , Caroline A. Cuoco , Alice L. Rodriguez , Emily Days , Paige N. Vinson , Krystian A. Kozek , C David Weaver , Anna L. Blobaum , Jeff Conn , Colleen M. Niswender , Craig W. Lindsley* .

Journal Name: Letters in Drug Design & Discovery

Become EABM
Become Reviewer


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).

Result: 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: mGlu2/4 , metabotropic glutamate receptor, Positive allosteric modulator (PAM), Heterodimer, Structure-Activity Relationship (SAR)

Rights & PermissionsPrintExport Cite as

Article Details

(E-pub Ahead of Print)
DOI: 10.2174/1570180815666181017131349

Article Metrics

PDF: 2