TY - JOUR
T1 - Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 3. Effect of replacing the inner polymethylene chain with cyclic moieties
AU - Tumiatti, Vincenzo
AU - Andrisano, Vincenza
AU - Banzi, Rita
AU - Bartolini, Manuela
AU - Minarini, Anna
AU - Rosini, Michela
AU - Melchiorre, Carlo
PY - 2004/12/16
Y1 - 2004/12/16
N2 - In the present paper we expanded SAR studies of 3, the ethyl analogue of the AChE inhibitor caproctamine (2), by investigating the role of its octamethylene spacer separating the two amide functions through the replacement with dipiperidine and dianiline moieties. Compounds 4 and 8 were the most interesting of the two series of compounds. Compound 4 was the most potent AChE inhibitor with a pIC50 value of 8.48 ± 0.02, while displaying also significant muscarinic M2 antagonistic activity (pKb, value of 6.18 ± 0.20). The availability of a suitable assay allowed us to verify whether 2, 3, 4, and 8 inhibit AChE-induced Aβ aggregation. Although all four derivatives caused a mixed type of AChE inhibition (active site and PAS), only 4 and 8, which bear an inner constrained spacer, were able to inhibit AChE-induced Aβ aggregation to a greater extent than donepezil. Clearly, the ability of an AChE inhibitor, based on a linear polyamine backbone, to bind both AChE sites may not be a sufficient condition to inhibit also AChE-induced Aβ aggregation. Dipiperidine derivative 4 emerged as a valuable pharmacological tool and a promising lead compound for new ligands to investigate and, hopefully, treat Alzheimer's disease.
AB - In the present paper we expanded SAR studies of 3, the ethyl analogue of the AChE inhibitor caproctamine (2), by investigating the role of its octamethylene spacer separating the two amide functions through the replacement with dipiperidine and dianiline moieties. Compounds 4 and 8 were the most interesting of the two series of compounds. Compound 4 was the most potent AChE inhibitor with a pIC50 value of 8.48 ± 0.02, while displaying also significant muscarinic M2 antagonistic activity (pKb, value of 6.18 ± 0.20). The availability of a suitable assay allowed us to verify whether 2, 3, 4, and 8 inhibit AChE-induced Aβ aggregation. Although all four derivatives caused a mixed type of AChE inhibition (active site and PAS), only 4 and 8, which bear an inner constrained spacer, were able to inhibit AChE-induced Aβ aggregation to a greater extent than donepezil. Clearly, the ability of an AChE inhibitor, based on a linear polyamine backbone, to bind both AChE sites may not be a sufficient condition to inhibit also AChE-induced Aβ aggregation. Dipiperidine derivative 4 emerged as a valuable pharmacological tool and a promising lead compound for new ligands to investigate and, hopefully, treat Alzheimer's disease.
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U2 - 10.1021/jm0494366
DO - 10.1021/jm0494366
M3 - Article
C2 - 15588084
AN - SCOPUS:10644228563
VL - 47
SP - 6490
EP - 6498
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 26
ER -