Tags

Type your tag names separated by a space and hit enter

Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives.
J Med Chem. 1998 Oct 08; 41(21):3976-86.JM

Abstract

Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

9767635

Citation

Rampa, A, et al. "Acetylcholinesterase Inhibitors: Synthesis and Structure-activity Relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- Methyl]aminoalkoxyheteroaryl Derivatives." Journal of Medicinal Chemistry, vol. 41, no. 21, 1998, pp. 3976-86.
Rampa A, Bisi A, Valenti P, et al. Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives. J Med Chem. 1998;41(21):3976-86.
Rampa, A., Bisi, A., Valenti, P., Recanatini, M., Cavalli, A., Andrisano, V., Cavrini, V., Fin, L., Buriani, A., & Giusti, P. (1998). Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives. Journal of Medicinal Chemistry, 41(21), 3976-86.
Rampa A, et al. Acetylcholinesterase Inhibitors: Synthesis and Structure-activity Relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- Methyl]aminoalkoxyheteroaryl Derivatives. J Med Chem. 1998 Oct 8;41(21):3976-86. PubMed PMID: 9767635.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives. AU - Rampa,A, AU - Bisi,A, AU - Valenti,P, AU - Recanatini,M, AU - Cavalli,A, AU - Andrisano,V, AU - Cavrini,V, AU - Fin,L, AU - Buriani,A, AU - Giusti,P, PY - 1998/10/10/pubmed PY - 1998/10/10/medline PY - 1998/10/10/entrez SP - 3976 EP - 86 JF - Journal of medicinal chemistry JO - J Med Chem VL - 41 IS - 21 N2 - Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9767635/Acetylcholinesterase_inhibitors:_synthesis_and_structure_activity_relationships_of_omega_[N_methyl_N__3_alkylcarbamoyloxyphenyl___methyl]aminoalkoxyheteroaryl_derivatives_ L2 - https://doi.org/10.1021/jm9810046 DB - PRIME DP - Unbound Medicine ER -