The Design, Synthesis and Pharmacological Characterization of Potent Xanomeline-Based M ₁ and M ₄ mAChR Bitopic Ligands

R) positive allosteric modulator MK cpd-97. Herein, we report on the design, synthesis, and pharmacological evaluation of a series of bitopic ligands featuring various aliphatic linkers. Derivatives with different linker lengths and types were tested across muscarinic receptor subtypes. Polymethylene-linked compounds showed minimal signaling bias and poor subtype selectivity, whereas PEG and polyamide linkers improved both properties. Notably, bitopic ligands incorporating diglycyl polyamide linkers exhibited the highest subtype preference with pronounced signaling bias. These findings provide insights into muscarinic ligand-receptor interactions and offer guidance for future bitopic ligand development.