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Article 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 heterodimer (EC = 3.4 μM), but was peripherally restricted (rat K = 0.03). Optimization of this hit led to PAMs with improved potency (ECs <800 nM) and improved CNS penetration (rat Kp >, 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 mGlu PAMs (secondary and tertiary amides) and not selective mGlu 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059629 | PMC |
| http://dx.doi.org/10.2174/1570180815666181017131349 | DOI Listing |
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Article Synopsis
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- Researchers utilized cryo-electron microscopy to reveal four distinct structures of the mGlu2-4 heterodimer, showcasing different activation states, including inactive, intermediate, and active forms.
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