title: Novel M(1) allosteric ligands: a patent review.
abstract: BACKGROUND
  There is substantial evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M(1) muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD) and antipsychotic models of schizophrenia. For example, a number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M(2) to M(5) subtypes. Thus, there is a need to identify selective activators of the M(1) receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M(1) is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site.
  
  
  METHODS
  This review discusses the M(1) muscarinic receptor and its potential therapeutic value in the treatment of CNS disorders such as AD and schizophrenia. Specifically, novel allosteric ligands that activate or positively modulate the M(1) receptor are examined and peer-reviewed articles associated with these patents publications are also described.
  
  
  CONCLUSIONS
  There is substantial evidence supporting activation of the M(1) receptor might be effective in treating symptoms of AD and schizophrenia, but therapeutic success has been elusive and is hypothesized to be due to the lack of selectivity among orthosteric agonists. During the past decade, allosteric modulation of GPCRs has evolved as a viable strategy toward generating subtype selective molecules. A number of novel, selective ligands in the form of allosteric agonists and positive allosteric modulators of the M(1) receptor have been identified offering the potential for clinical evaluation of M(1)-specific receptor activation.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories , Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. scott_d_kuduk@merck.com
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Beshore
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D003071:Cognition / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008568:Memory / Q000187:drug effects; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D018697:Nootropic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010330:Patents as Topic; D011487:Protein Conformation; D043643:Receptor, Muscarinic M1 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D018721:Muscarinic Agonists; D018697:Nootropic Agents; D043643:Receptor, Muscarinic M1