Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease.

Gerard Esteban; Jennifer Allan; Abdelouahid Samadi; Andrea Mattevi; Mercedes Unzeta; José Marco-Contelles; Claudia Binda; Rona R. Ramsay

doi:10.1016/j.bbapap.2014.03.006

Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease.

Translated title of the contribution: Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease.

Gerard Esteban, Jennifer Allan, Abdelouahid Samadi, Andrea Mattevi, Mercedes Unzeta, José Marco-Contelles, Claudia Binda, Rona R. Ramsay

Department of Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › Research › peer-review

50 Citations (Scopus)

Abstract

Monoamine oxidases (MAO) and cholinesterases are validated targets in the design of drugs for the treatment of Alzheimer's disease. The multi-target compound N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl) methyl)-N-methylprop-2-yn-1-amine (ASS234), bearing the MAO-inhibiting propargyl group attached to a donepezil moiety that inhibits cholinesterases, retained activity against human acetyl- and butyryl-cholinesterases. The inhibition of MAO A and MAO B by ASS234 was characterized and compared to other known MAO inhibitors. ASS234 was almost as effective as clorgyline (kinact/ KI = 3 × 106 min- 1 M- 1) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor. © 2014 Elsevier B.V.

Translated title of the contribution	Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease.
Original language	Multiple languages
Pages (from-to)	1104-1110
Journal	Biochimica et Biophysica Acta - Proteins and Proteomics
Volume	1844
Issue number	6
DOIs	https://doi.org/10.1016/j.bbapap.2014.03.006 https://doi.org/10.1016/j.bbapap.2014.03.006.
Publication status	Published - 1 Jan 2014

Keywords

Alzheimer's disease
ASS234
Crystal structure
Flavin adduct
Multi-target drug
PF9601N

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Esteban, G., Allan, J., Samadi, A., Mattevi, A., Unzeta, M., Marco-Contelles, J., Binda, C., & Ramsay, R. R. (2014). Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease. Biochimica et Biophysica Acta - Proteins and Proteomics, 1844(6), 1104-1110. https://doi.org/10.1016/j.bbapap.2014.03.006, https://doi.org/10.1016/j.bbapap.2014.03.006.

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title = "Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease.",

abstract = "Monoamine oxidases (MAO) and cholinesterases are validated targets in the design of drugs for the treatment of Alzheimer's disease. The multi-target compound N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl) methyl)-N-methylprop-2-yn-1-amine (ASS234), bearing the MAO-inhibiting propargyl group attached to a donepezil moiety that inhibits cholinesterases, retained activity against human acetyl- and butyryl-cholinesterases. The inhibition of MAO A and MAO B by ASS234 was characterized and compared to other known MAO inhibitors. ASS234 was almost as effective as clorgyline (kinact/ KI = 3 × 106 min- 1 M- 1) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor. {\textcopyright} 2014 Elsevier B.V.",

keywords = "Alzheimer's disease, ASS234, Crystal structure, Flavin adduct, Multi-target drug, PF9601N",

author = "Gerard Esteban and Jennifer Allan and Abdelouahid Samadi and Andrea Mattevi and Mercedes Unzeta and Jos{\'e} Marco-Contelles and Claudia Binda and Ramsay, {Rona R.}",

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Esteban, G, Allan, J, Samadi, A, Mattevi, A, Unzeta, M, Marco-Contelles, J, Binda, C & Ramsay, RR 2014, 'Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease.', Biochimica et Biophysica Acta - Proteins and Proteomics, vol. 1844, no. 6, pp. 1104-1110. https://doi.org/10.1016/j.bbapap.2014.03.006, https://doi.org/10.1016/j.bbapap.2014.03.006.

Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease. / Esteban, Gerard; Allan, Jennifer; Samadi, Abdelouahid et al.
In: Biochimica et Biophysica Acta - Proteins and Proteomics, Vol. 1844, No. 6, 01.01.2014, p. 1104-1110.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease.

AU - Esteban, Gerard

AU - Allan, Jennifer

AU - Samadi, Abdelouahid

AU - Mattevi, Andrea

AU - Unzeta, Mercedes

AU - Marco-Contelles, José

AU - Binda, Claudia

AU - Ramsay, Rona R.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Monoamine oxidases (MAO) and cholinesterases are validated targets in the design of drugs for the treatment of Alzheimer's disease. The multi-target compound N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl) methyl)-N-methylprop-2-yn-1-amine (ASS234), bearing the MAO-inhibiting propargyl group attached to a donepezil moiety that inhibits cholinesterases, retained activity against human acetyl- and butyryl-cholinesterases. The inhibition of MAO A and MAO B by ASS234 was characterized and compared to other known MAO inhibitors. ASS234 was almost as effective as clorgyline (kinact/ KI = 3 × 106 min- 1 M- 1) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor. © 2014 Elsevier B.V.

AB - Monoamine oxidases (MAO) and cholinesterases are validated targets in the design of drugs for the treatment of Alzheimer's disease. The multi-target compound N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl) methyl)-N-methylprop-2-yn-1-amine (ASS234), bearing the MAO-inhibiting propargyl group attached to a donepezil moiety that inhibits cholinesterases, retained activity against human acetyl- and butyryl-cholinesterases. The inhibition of MAO A and MAO B by ASS234 was characterized and compared to other known MAO inhibitors. ASS234 was almost as effective as clorgyline (kinact/ KI = 3 × 106 min- 1 M- 1) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor. © 2014 Elsevier B.V.

KW - Alzheimer's disease

KW - ASS234

KW - Crystal structure

KW - Flavin adduct

KW - Multi-target drug

KW - PF9601N

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DO - 10.1016/j.bbapap.2014.03.006

M3 - Artículo

SN - 1570-9639

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EP - 1110

JO - Biochimica et Biophysica Acta - Proteins and Proteomics

JF - Biochimica et Biophysica Acta - Proteins and Proteomics

IS - 6

ER -

Esteban G, Allan J, Samadi A, Mattevi A, Unzeta M, Marco-Contelles J et al. Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease. Biochimica et Biophysica Acta - Proteins and Proteomics. 2014 Jan 1;1844(6):1104-1110. doi: 10.1016/j.bbapap.2014.03.006, 10.1016/j.bbapap.2014.03.006.

Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease.

Abstract

Keywords

UN SDGs

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