Flohr Alexander, Hutter Roman, Mueller Barbara, Bohnert Claudia, Pellisson Mélanie, Schaffhauser Hervé
Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
Bioorg Med Chem Lett. 2017 Dec 15;27(24):5415-5419. doi: 10.1016/j.bmcl.2017.11.008. Epub 2017 Nov 6.
Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer's disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM's) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor. Low-shift PAM's offer the potential of "use-dependent" attenuation of transmitter-signaling while avoiding pseudo-agonistic behavior in vivo as a common limitation of the so far described high-shift PAM's. With these novel M1-PAM's, the M1 receptor is potentially the first GPCR for which both, high- and low shift PAM's have become available.
毒蕈碱M1受体的正向调节长期以来吸引着科学家和药物研发人员，有望用于治疗阿尔茨海默病或精神分裂症。然而，由于M1受体激动剂和正向变构调节剂（PAM）都存在副作用，M1激活的认知前潜力尚未得到临床证实。为避免M1受体过度激活，我们设计了一种新的筛选形式，并开发了首个用于M1受体的低位移正向变构调节剂。低位移PAM具有“使用依赖性”减弱递质信号的潜力，同时避免了体内拟激动行为，而这是目前所描述的高位移PAM常见的局限性。有了这些新型M1-PAM，M1受体可能是首个同时有高位移和低位移PAM的GPCR。
