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Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 3. Effect of replacing the inner polymethylene chain with cyclic moieties.
J Med Chem. 2004 Dec 16; 47(26):6490-8.JM

Abstract

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 Abeta 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 Abeta 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 Abeta 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.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. vincenzo.tumiatti@unibo.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15588084

Citation

Tumiatti, Vincenzo, et al. "Structure-activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based On a Polyamine Backbone. 3. Effect of Replacing the Inner Polymethylene Chain With Cyclic Moieties." Journal of Medicinal Chemistry, vol. 47, no. 26, 2004, pp. 6490-8.
Tumiatti V, Andrisano V, Banzi R, et al. Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 3. Effect of replacing the inner polymethylene chain with cyclic moieties. J Med Chem. 2004;47(26):6490-8.
Tumiatti, V., Andrisano, V., Banzi, R., Bartolini, M., Minarini, A., Rosini, M., & Melchiorre, C. (2004). Structure-activity relationships of acetylcholinesterase noncovalent inhibitors based on a polyamine backbone. 3. Effect of replacing the inner polymethylene chain with cyclic moieties. Journal of Medicinal Chemistry, 47(26), 6490-8.
Tumiatti V, et al. Structure-activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based On a Polyamine Backbone. 3. Effect of Replacing the Inner Polymethylene Chain With Cyclic Moieties. J Med Chem. 2004 Dec 16;47(26):6490-8. PubMed PMID: 15588084.
* Article titles in AMA citation format should be in sentence-case
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 - 2004/12/14/pubmed PY - 2005/1/19/medline PY - 2004/12/14/entrez SP - 6490 EP - 8 JF - Journal of medicinal chemistry JO - J Med Chem VL - 47 IS - 26 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 Abeta 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 Abeta 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 Abeta 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. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/15588084/Structure_activity_relationships_of_acetylcholinesterase_noncovalent_inhibitors_based_on_a_polyamine_backbone__3__Effect_of_replacing_the_inner_polymethylene_chain_with_cyclic_moieties_ L2 - https://doi.org/10.1021/jm0494366 DB - PRIME DP - Unbound Medicine ER -