Structural Features of Iperoxo-BQCA Muscarinic Acetylcholine Receptor Hybrid Ligands Determining Subtype Selectivity and Efficacy.

Selective agonists for the human M 1 and M 4 muscarinic acetylcholine receptors (mAChRs) are attractive candidates for the treatment of cognitive disorders, such as Alzheimer's disease and schizophrenia. Past efforts to optimize a ligand for selective agonism at any one of the M 1 -M 5 mAChR subtypes has proven to be a significant challenge. Recently, research efforts have demonstrated that hybrid ligands may offer a potential solution to the lack of selectivity at mAChRs. In an attempt to design M 1 mAChR selective agonists by hybridizing an M 1 mAChR selective positive allosteric modulator [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] and a potent agonist [(4-[(4,5-dihydro-3-isoxazolyl)oxy]- N , N , N -trimethyl-2-butyn-1-aminium iodide) (iperoxo)], we unexpectedly discovered that these ligands possessed noticeable M 2 /M 4 mAChR selectivity. Evaluation of truncated derivatives of the hybrid ligands at the M 1 -M 5 mAChR subtypes suggests that the allosteric pharmacophore of iperoxo-based mAChR hybrid ligands likely sterically disrupts the allosteric site of the mAChRs, attenuating the efficacy of M 1 /M 3 /M 5 mAChR responses compared to M 2 /M 4 mAChRs, resulting in a preference for the M 2 /M 4 mAChRs. However, at certain intermediate linker lengths, the effects of this apparent disruption of the allosteric site are diminished, restoring nonselective agonism and suggesting a possible allosteric interaction which is favorable to efficacy at all M 1 -M 5 mAChRs.