Orthosteric/Allosteric Bitopic Ligands

Functional selectivity as a consequence of a bitopic mechanism. Combination of the allosteric modulator DDBL-4 and orthosteric agonist TMA recapitulates the pharmacology of McN-A-343, a functionally selective muscarinic receptor agonist. (A) Effects of the indicated ligands on M₂ or M₁ muscarinic receptor–mediated ERK1/2 phosphorylation. DDBL-4 is a negative allosteric modulator of TMA efficacy at the M₂ receptor but has a minimal effect at the M₁ receptor, presumably due to differences between allosteric sites. Data for the M₂ receptor are adapted from (44). (B) Mutation within the prototypical allosteric site of the M₂ receptor reduces the potency of DDBL-4 as a negative efficacy modulator and increases the efficacy of McN-A-343; the dashed line indicates agonist behavior at the wild-type M₂ receptor. Data are adapted from (44) (FBS, fetal bovine serum.)