Muscarinic receptor 1 agonist activity of novel N-aryl carboxamide substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models

Manish Malviya; Y C Sunil Kumar; R B Mythri; C Venkateshappa; M N Subhash; K S Rangappa

doi:10.1016/j.bmc.2009.06.032

Muscarinic receptor 1 agonist activity of novel N-aryl carboxamide substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models

Bioorg Med Chem. 2009 Aug 1;17(15):5526-34. doi: 10.1016/j.bmc.2009.06.032. Epub 2009 Jun 21.

Authors

Manish Malviya¹, Y C Sunil Kumar, R B Mythri, C Venkateshappa, M N Subhash, K S Rangappa

Affiliation

¹ Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, Karnataka, India.

PMID: 19595599
DOI: 10.1016/j.bmc.2009.06.032

Abstract

Earlier we have reported the effect of arecoline thiazolidinone and morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer's presenile dementia models. To elucidate further our Structure-Activity Relationship (SAR) studies on the chemistry and muscarinic receptor 1 binding efficacy, a series of novel carboxamide derivatives of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine molecule have been designed and synthesized as a new class of M1 receptor agonists with a low toxicity effect profile that enhances memory function in animal models of Alzheimer's presenile dementia and also modulates the APP secretion from rat brain cerebrocortical slices by activating M1 receptor in vitro. Results suggest that compound 9b having methyl group at the para position of the aryl group attached to the carboxamide of morpholino arecoline could emerge as a potent molecule having antidementia activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy*
Amyloid beta-Protein Precursor / metabolism
Animals
Arecoline / chemical synthesis
Arecoline / chemistry*
Arecoline / pharmacology
Arecoline / therapeutic use
Cerebral Cortex / drug effects
Cerebral Cortex / metabolism
Dose-Response Relationship, Drug
Humans
Inositol 1,4,5-Trisphosphate / metabolism
Male
Maze Learning / drug effects
Memory Disorders / chemically induced
Memory Disorders / drug therapy
Morpholines / chemical synthesis
Morpholines / chemistry*
Morpholines / pharmacology
Morpholines / therapeutic use
Muscarinic Agonists / chemical synthesis
Muscarinic Agonists / chemistry*
Muscarinic Agonists / pharmacology
Muscarinic Agonists / therapeutic use*
Protein Binding
Rats
Rats, Wistar
Receptor, Muscarinic M1 / agonists
Receptor, Muscarinic M1 / metabolism*
Structure-Activity Relationship

Substances

Amyloid beta-Protein Precursor
Morpholines
Muscarinic Agonists
Receptor, Muscarinic M1
Arecoline
Inositol 1,4,5-Trisphosphate
morpholine