Discovery of the first low-shift positive allosteric modulators for the muscarinic M1 receptor

  • Bioorg Med Chem Lett. 2017 Dec 15;27(24):5415-5419. doi: 10.1016/j.bmcl.2017.11.008.
Alexander Flohr  1 ,  Roman Hutter  2 ,  Barbara Mueller  2 ,  Claudia Bohnert  2 ,  Mélanie Pellisson  2 ,  Hervé Schaffhauser  2
Affiliations
  • 1. Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland. Electronic address: [email protected].
  • 2. Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
PMID: 29146472 DOI: 10.1016/j.bmcl.2017.11.008
Abstract

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.

Keywords
Allosteric; Cognition; GPCR; M1; Modulator; Muscarinic.
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