The antipsychotic potential of muscarinic allosteric modulation

Thomas M. Bridges, Evan P. LeBois, Corey R Hopkins, Michael R. Wood, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley

Research output: Contribution to journalReview article

43 Citations (Scopus)

Abstract

The cholinergic hypothesis of schizophrenia emerged over 50 years ago based on clinical observations with both anticholinergics and pan-muscarinic agonists. Not until the 1990s did the cholinergic hypothesis of schizophrenia receive renewed enthusiasm based on clinical data with xanomeline, a muscarinic acetylcholine receptor M1/M4-preferring orthosteric agonist. In a clinical trial with Alzheimer's patients, xanomeline not only improved cognitive performance, but also reduced psychotic behaviors. This encouraging data spurred a second clinical trial in schizophrenic patients, wherein xanomeline significantly improved the positive, negative and cognitive symptom clusters. However, the question remained: Was the antipsychotic efficacy due to activation of M1, M4 or both M1/M 4? Classical orthosteric ligands lacked the muscarinic receptor subtype selectivity required to address this key question. More recently, functional assays have allowed for the discovery of ligands that bind at allosteric sites, binding sites distinct from the orthosteric (acetylcholine) site, which are structurally less conserved and thereby afford high levels of receptor subtype selectivity. Recently, allosteric ligands, with unprecedented selectivity for either M1 or M4, have been discovered and have demonstrated comparable efficacy to xanomeline in preclinical antipsychotic and cognition models. These data suggest that selective allosteric activation of either M1 or M4 has antipsychotic potential through distinct, yet complimentary mechanisms.

Original languageEnglish (US)
Pages (from-to)229-240
Number of pages12
JournalDrug News and Perspectives
Volume23
Issue number4
DOIs
StatePublished - May 1 2010

Fingerprint

xanomeline
Cholinergic Agents
Antipsychotic Agents
Muscarinic Receptors
Ligands
Schizophrenia
Clinical Trials
Muscarinic M1 Receptors
Allosteric Site
Muscarinic Agonists
Neurobehavioral Manifestations
Cholinergic Antagonists
Cognition
Acetylcholine
Binding Sites

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Bridges, T. M., LeBois, E. P., Hopkins, C. R., Wood, M. R., Jones, C. K., Conn, P. J., & Lindsley, C. W. (2010). The antipsychotic potential of muscarinic allosteric modulation. Drug News and Perspectives, 23(4), 229-240. https://doi.org/10.1358/dnp.2010.23.4.1416977

The antipsychotic potential of muscarinic allosteric modulation. / Bridges, Thomas M.; LeBois, Evan P.; Hopkins, Corey R; Wood, Michael R.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.

In: Drug News and Perspectives, Vol. 23, No. 4, 01.05.2010, p. 229-240.

Research output: Contribution to journalReview article

Bridges, TM, LeBois, EP, Hopkins, CR, Wood, MR, Jones, CK, Conn, PJ & Lindsley, CW 2010, 'The antipsychotic potential of muscarinic allosteric modulation', Drug News and Perspectives, vol. 23, no. 4, pp. 229-240. https://doi.org/10.1358/dnp.2010.23.4.1416977
Bridges, Thomas M. ; LeBois, Evan P. ; Hopkins, Corey R ; Wood, Michael R. ; Jones, Carrie K. ; Conn, P. Jeffrey ; Lindsley, Craig W. / The antipsychotic potential of muscarinic allosteric modulation. In: Drug News and Perspectives. 2010 ; Vol. 23, No. 4. pp. 229-240.
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