Capsaicinoids

This review analyses the application of medicinal chemistry in the modulation of G-protein-coupled receptor (GPCR) targets in the treatment of neurological disorders based on the presentation of preclinical evidence provided solely by animals. Considering dopaminergic, serotonergic and glutamatergic systems, we combine outcomes of rodents, zebrafish and non-human primates in demonstrating how optimization of structure-activity relationships (SAR), allosteric/bitopic and biased-ligand development, scaffold hopping and ADMET tuning yield brain-penetrant ligands with enhanced affinity, subtype selectivity, signalling bias and pharmacokinetic. The product shows promise in restoring motor function and reducing oxidative stress in D2/D3 modulators of 6-OHDA Parkinsonian rat models, as well as anxiolytic and antidepressant-like actions of engineered 5-HT1A/5-HT2A ligands in mice and zebrafish. Additionally, it exhibits precognitive and neuroprotective actions of mGluR PAMs in APP/PS1 and scopolamine models. We emphasize methodological strategies (in vitro binding, behavioural assays, microdialysis, PK/autoradiography) that can be used to bridge molecular design to organismal response, explain the translational obstacles affecting translation that include species differences, crosstalk and long-term signalling responses, and suggest prospects including AI-guided design, multi-omics biomarkers and targeted CNS delivery protocols. The arguments put forward make medicinal chemistry one of the key, mechanism-oriented catalysts in the evolution of GPCR-targeted neurotherapeutics.