Literature DB >> 18593778

Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia.

Anantha Shekhar1, William Z Potter, Jeffrey Lightfoot, John Lienemann, Sanjay Dubé, Craig Mallinckrodt, Frank P Bymaster, David L McKinzie, Christian C Felder.   

Abstract

OBJECTIVE: There are significant unmet needs in the treatment of schizophrenia, especially for the treatment of cognitive impairment, negative syndrome, and cognitive function. Preclinical data suggest that agonists with selective affinity for acetylcholine muscarinic receptors provide a potentially new mechanism to treat schizophrenia. The authors studied xanomeline, a relatively selective muscarinic type 1 and type 4 (M(1) and M(4)) receptor agonist, to determine if this agent is effective in the treatment of schizophrenia.
METHOD: In this pilot study, the authors examined the efficacy of xanomeline on clinical outcomes in subjects with schizophrenia (N=20) utilizing a double-blind, placebo-controlled, 4-week treatment design. Outcome measures included the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI) scale, and a test battery designed to measure cognitive function in patients with schizophrenia.
RESULTS: Subjects treated with xanomeline did significantly better than subjects in the placebo group on total BPRS scores and total PANSS scores. In the cognitive test battery, subjects in the xanomeline group showed improvements most robustly in measures of verbal learning and short-term memory function.
CONCLUSIONS: These results support further investigation of xanomeline as a novel approach to treating schizophrenia.

Entities:  

Mesh:

Substances:

Year:  2008        PMID: 18593778     DOI: 10.1176/appi.ajp.2008.06091591

Source DB:  PubMed          Journal:  Am J Psychiatry        ISSN: 0002-953X            Impact factor:   18.112


  154 in total

1.  Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071.

Authors:  Evan P Lebois; Gregory J Digby; Douglas J Sheffler; Bruce J Melancon; James C Tarr; Hyekyung P Cho; Nicole R Miller; Ryan Morrison; Thomas M Bridges; Zixiu Xiang; J Scott Daniels; Michael R Wood; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2011-08-24       Impact factor: 2.823

2.  A Monod-Wyman-Changeux mechanism can explain G protein-coupled receptor (GPCR) allosteric modulation.

Authors:  Meritxell Canals; J Robert Lane; Adriel Wen; Peter J Scammells; Patrick M Sexton; Arthur Christopoulos
Journal:  J Biol Chem       Date:  2011-11-15       Impact factor: 5.157

3.  Discovery of potential antipsychotic agents possessing pro-cognitive properties.

Authors:  Jelveh Lameh; Krista McFarland; Jorgen Ohlsson; Fredrik Ek; Fabrice Piu; Ethan S Burstein; Ali Tabatabaei; Roger Olsson; Stefania Risso Bradley; Douglas W Bonhaus
Journal:  Naunyn Schmiedebergs Arch Pharmacol       Date:  2011-11-15       Impact factor: 3.000

4.  Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M(1) receptor function in the central nervous system.

Authors:  Evan P Lebois; Thomas M Bridges; L Michelle Lewis; Eric S Dawson; Alexander S Kane; Zixiu Xiang; Satyawan B Jadhav; Huiyong Yin; J Phillip Kennedy; Jens Meiler; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; C David Weaver; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2010       Impact factor: 4.418

Review 5.  Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia.

Authors:  Carrie K Jones; Nellie Byun; Michael Bubser
Journal:  Neuropsychopharmacology       Date:  2011-09-28       Impact factor: 7.853

6.  Antipsychotic drugs activate the C. elegans akt pathway via the DAF-2 insulin/IGF-1 receptor.

Authors:  Kathrine R Weeks; Donard S Dwyer; Eric J Aamodt
Journal:  ACS Chem Neurosci       Date:  2010-03-25       Impact factor: 4.418

7.  Structural determinants of allosteric agonism and modulation at the M4 muscarinic acetylcholine receptor: identification of ligand-specific and global activation mechanisms.

Authors:  Vindhya Nawaratne; Katie Leach; Christian C Felder; Patrick M Sexton; Arthur Christopoulos
Journal:  J Biol Chem       Date:  2010-04-20       Impact factor: 5.157

Review 8.  The antipsychotic potential of muscarinic allosteric modulation.

Authors:  Thomas M Bridges; Evan P LeBois; Corey R Hopkins; Michael R Wood; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley
Journal:  Drug News Perspect       Date:  2010-05

9.  Cortical M1 receptor concentration increases without a concomitant change in function in Alzheimer's disease.

Authors:  Cassia R Overk; Christian C Felder; Yuan Tu; Doug A Schober; Kelly R Bales; Joanne Wuu; Elliott J Mufson
Journal:  J Chem Neuroanat       Date:  2010-03-27       Impact factor: 3.052

Review 10.  Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders.

Authors:  Gregory J Digby; Jana K Shirey; P Jeffrey Conn
Journal:  Mol Biosyst       Date:  2010-06-25
View more

北京卡尤迪生物科技股份有限公司 © 2022-2023.