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

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

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).

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.

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