Discovery of 2‐Aminothiazole‐4‐carboxamides, a Novel Class of Muscarinic M₃ Selective Antagonists, Through Solution‐Phase Parallel Synthesis.

Abstract

Selective Antagonists, Through Solution-Phase Parallel Synthesis. -M3 selective antagonists are obtained by derivatization of the lead structure of the in-house chemical collection utilizing a combinatorial approach. The solution-phase parallel synthesis effectively contributes to the optimization of each segment of the lead. A representative procedure shows the preparation of aminothiazole derivative (VIII). Thiazoles (VIII) and (IX) exhibit potent binding affinities for M3 receptors, together with greater than 100-fold selectivity for M3 over M1 and M2 receptors. -(SAGARA, Y.; MITSUYA, M.; UCHIYAMA, M.; OGINO, Y.; KIMURA, T.; OHTAKE*, N.; MASE, T.; Chem.

Allosteric Effects of Sodium Ion Binding on Activation of the M3 Muscarinic G-Protein-Coupled Receptor

“…For the M3 muscarinic receptor, experimental mutation of D2.50 to asparagine showed increased binding affinity of the nitrogen mustard analogs of the acetylcholine and McN-A-343 agonists (30), suggesting that the D2.50N mutation biases the M3 receptor toward the active conformational state. Random mutagenesis of the M3 receptor also suggested a conformational link between the highly conserved D2.50, R3.50, and Y5.58 residues that is critical for receptor activation and G-protein coupling (31,32).…”