posted on 2021-12-14, 22:13authored byMatthew
C. L. Wakeham, Briana J. Davie, David K. Chalmers, Arthur Christopoulos, Ben Capuano, Celine Valant, Peter J. Scammells
Selective
agonists for the human M1 and M4 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 M1–M5 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
M1 mAChR selective agonists by hybridizing an M1 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 M2/M4 mAChR selectivity.
Evaluation of truncated derivatives of the hybrid ligands at the M1–M5 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 M1/M3/M5 mAChR responses compared
to M2/M4 mAChRs, resulting in a preference for
the M2/M4 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 M1–M5 mAChRs.