Abstract
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 The ester group of arecoline (which is reported as muscarinic agonist) has been replaced by N-substituted morpholine ring. The structure activity relationship reveals that the electron donating 4-substituted sulfonyl derivatives (9a, 9b, 9c, and 9e) on the nitrogen atom of the morpholine ring increases the affinity of M1 receptor binding 50- to 80-fold greater than the corresponding arecoline. Other derivatives also showed considerable M1 receptor binding affinity. (C) 2008 Elsevier Ltd. All rights reserved.
Highlights
Neurochemical examination of the brain material from patients having Alzheimer’s disease (AD) has demonstrated the loss of the presynaptic marker enzyme, choline acetyltransferase, and the muscarinic receptors of the M2 subtype which are mainly responsible for causing deficits in central cholinergic transmission in Alzheimer’s patients.[1,2,3] The postsynaptic muscarinic receptors, which are primarily of the M1 subtype, seem to a large extent to survive the loss of cholinergic nerve endings.[4]
A structure–activity relationship (SAR) can be drawn from the in vitro affinity assay for the synthesized N-arylurea- substituted 3-morpholino arecoline derivatives 9(a-j)
When the same is introduced at an ortho- (9a) or a para- (9c) position it reduces the affinity of the compound towards the M1 receptor
Summary
Neurochemical examination of the brain material from patients having Alzheimer’s disease (AD) has demonstrated the loss of the presynaptic marker enzyme, choline acetyltransferase, and the muscarinic receptors of the M2 subtype which are mainly responsible for causing deficits in central cholinergic transmission in Alzheimer’s patients.[1,2,3] The postsynaptic muscarinic receptors, which are primarily of the M1 subtype, seem to a large extent to survive the loss of cholinergic nerve endings.[4]. The Nbenzyl group of 5 was removed by refluxing in methanol in the presence of 10% Pd-C and ammonium formate, and the resulting free amine was treated with Boc-anhydride in THF in the presence of K2CO3 to yield the Boc-protected compound 6. This was converted by reaction with methyl iodide in acetone into the corresponding methylamine hydro-iodide salt. This on treatment with sodium borohydride in methanol gave the reduced product 7. All the synthesized compounds were characterized by IR, 1H NMR, mass spectroscopy, and CHN analysis
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