1. Discovery of the first low-shift positive allosteric modulators for the muscarinic M1 receptor
- Author
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Alexander Flohr, Barbara Mueller, Hervé Schaffhauser, Roman Hutter, Claudia Bohnert, and Mélanie Pellisson
- Subjects
0301 basic medicine ,Clinical Biochemistry ,Allosteric regulation ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,CHO Cells ,Pharmacology ,Muscarinic Agonists ,Biochemistry ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Cricetulus ,Allosteric Regulation ,Cricetinae ,parasitic diseases ,Drug Discovery ,Muscarinic acetylcholine receptor ,Animals ,Humans ,GABA-A Receptor Agonists ,Molecular Biology ,G protein-coupled receptor ,Chemistry ,Organic Chemistry ,Receptor, Muscarinic M1 ,Muscarinic acetylcholine receptor M1 ,Receptors, GABA-A ,030104 developmental biology ,Mutagenesis, Site-Directed ,Molecular Medicine ,030217 neurology & neurosurgery - 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.
- Published
- 2017