Effect of Novel Amino Acids and Dipeptides Substituted 3-Morpholino Arecoline Derivatives as Muscarinic Receptor 1 Agonists in Alzheimer’s Dementia Models

A series of novel, potent and selective muscarinic receptor 1 agonists (M1 receptor agonists) that employ a key N -substituted morpholine arecoline moiety has been synthesized as part of research effort for the therapy of Alzheimer’s diseases. The ester group of arecoline (which is reported as mucar...

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Bibliographic Details
Published in:International journal of peptide research and therapeutics 2009-12, Vol.15 (4), p.323-337
Main Authors: Ranganatha, S. R., Malviya, Manish, Sunil Kumar, Y. C., Vinaya, K., Prasanna, D. S., Subhash, M. N., Rangappa, K. S.
Format: Article
Language:English
Subjects:
Alzheimer's disease
Amino acids
Animal Anatomy
Biochemistry
Biomedical and Life Sciences
Histology
Life Sciences
Molecular biology
Molecular Medicine
Morphology
Neurons
Peptides
Pharmaceutical Sciences/Technology
Pharmacology/Toxicology
Polymer Sciences
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Summary:A series of novel, potent and selective muscarinic receptor 1 agonists (M1 receptor agonists) that employ a key N -substituted morpholine arecoline moiety has been synthesized as part of research effort for the therapy of Alzheimer’s diseases. The ester group of arecoline (which is reported as mucarinic agonist) has been replaced by N- substituted morpholine ring. The structure activity relationship reveals that the increase in lipophilic carbon chain on the nitrogen atom of the morpholine ring increases the affinity of M1 receptor. In the present study, we are reporting N -amino acid substituted 9 ( a – k ) and dipeptides substituted 10 ( a – j ) and 11 ( a – j ) morpholino arecoline derivatives, along with their in vitro muscarinic binding studies by using [ 3 H]QNB and also in vivo evaluation of memory and learning in male Wistar rats (passive avoidance test plus maze studies) as M1 receptor agonist. Some molecules from the dipeptide series ( 10b , 10c and 10j ) showed potent M1 receptor agonist activity. Other derivatives also showed considerable M1 receptor binding affinity.
ISSN:1573-3149
1573-3904
DOI:10.1007/s10989-009-9194-z