Muscarinic receptor 1 agonist activity of novel N-aryl carboxamide substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models.
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.
Malviya
Manish
M
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, Karnataka, India.
Kumar
Y C Sunil
YC
Mythri
R B
RB
Venkateshappa
C
C
Subhash
M N
MN
Rangappa
K S
KS
D000544:Alzheimer Disease / Q000188:drug therapy*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001115:Arecoline / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
D016564:Amyloid beta-Protein Precursor; D009025:Morpholines; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D001115:Arecoline; D015544:Inositol 1,4,5-Trisphosphate; C037574:morpholine