Manka Marycleopha
Metabotropic glutamate receptor subtype 5 (mGlu5) is an important regulator of excitatory neurotransmission and remains a therapeutic target for neuropsychiatric and neurological disorders, including substance use disorders, depression, Fragile X syndrome, Parkinson's disease-related dyskinesia, and other movement disorders. However, the clinical development of mGlu5 negative allosteric modulators (NAMs) has been limited by translational challenges, inconsistent efficacy, and safety concerns, particularly hepatotoxicity associated with early acetylene-containing scaffolds such as ADX10059. The study provides an updated assessment of the mGlu5 NAM patent landscape and related medicinal chemistry advances from 2018 to the present. The post-2018 period is characterised as a phase of translational and medicinal chemistry refinement, marked by a shift from metabolically unstable aryl-alkyne and acetylene-based chemotypes towards more stable heterocyclic, bicyclic, and non-acetylene frameworks. Key strategies include scaffold hopping, structure-based drug design, receptor occupancy assessment, and pharmacokinetic optimisation to reduce the risk of bioactivation, improve brain exposure, and enhance clinical translatability. Recent patent-linked compounds such as TMP-301/HTL0014242, VU0424238, VU6031545, VU6024945, and AE90015 are presented alongside unconventional approaches, including GET-73, LCGM-10, antibodies, and nanobodies. It also covers clinical progress, including the repurposing of mavoglurant/STP7 for cocaine use disorder. Overall, the field aims for safer, more selective, and better-controlled mGlu5 modulation strategies, but challenges related to efficacy, tolerability, and patient selection continue to hinder clinical success.