Studies have demonstrated the presence of allosteric binding sites on each of the
muscarinic acetylcholine receptor (mAChR) subtypes. Since most drugs targeting
muscarinic receptors bind to the highly conserved orthosteric binding site, they fail to achieve appreciable subtype selectivity. Targeting non-conserved allosteric sites may provide a new way of enhancing selectivity for individual subtypes of
muscarinic receptor. Tetra(ethyleneglycol)(3-methoxy-1,2,5-thiadiazol-4-yl)[3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl]
ether,
CDD-0304 (10), was found to be a M₁/₂/₄ selective
muscarinic agonist and might prove useful in treating the symptoms associated with
schizophrenia (J. Med. Chem.2003, 46, 4273). It was hypothesized that the observed subtype selectivity demonstrated by 10 may be due to its ability to function as a bitopic
ligand (J. Med. Chem.2006, 49, 7518). To further investigate this possibility, a novel series of compounds was synthesized using a 1,2,5-thiadiazole moiety along with varying lengths of a
polyethylene glycol linker and terminal groups, for evaluation as potential allosteric modulators of
muscarinic receptors. Preliminary
biological studies were performed using
carbachol to stimulate M₁ and M₅ receptors. No significant agonist activity was observed at either M₁ or M₅ receptors for any of the compounds.
Compound 18, 2-(4-methoxy-1,2,5-thiadiazol-3-yloxy)-N,N-dimethylethanamine
fumarate (CDD-0361F) was found to block the effects of
carbachol at
M5 muscarinic receptors.