Orthosteric/Allosteric Bitopic Ligands

Bitopic ligand design as a means for optimized affinity or selectivity. (A) Effects of the bitopic ligand THRX-160209 and its constituent orthosteric (3-BHP) or allosteric (4-ABP) moieties on the binding of the orthosteric probe NMS at the M₂ muscarinic receptor. Adapted from from (43). (B) Loss of affinity, but gain in selectivity, as exemplified by the bitopic ligands, “hybrid 1” (2-{3-[1-(6-{1,1-Dimethyl-1-[4-(isoxazol-3-yloxy)but-2-ynyl]-ammonium}hexyl)-1,1 dimethylammonio]propyl}isoindoline-1,3-dione dibromide) and “hybrid 2” (2-{3-[1-(6-{1,1-Dimethyl-1-[4-(isoxazol-3-yloxy)but-2-ynyl]-ammonium}hexyl)-1,1-dimethylammonio]-2,2-dimethylpropyl}-benzo[de] isoquinoline-1,3-dione dibromide), relative to the non-selective orthosteric agonist iperoxo. Native muscarinic acetylcholine receptors are expressed in guinea pig left atrium (M₂), rabbit vas deferens (M₁), and guinea pig ileum (M₃). Adapted from (41).