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

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

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

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 (k_inact/K_I = 3 × 10⁶ min^− 1 M^− 1) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor.

Original language	English
Pages (from-to)	1104–1110
Number of pages	6
Journal	Biochimica et Biophysica Acta - Proteins and Proteomics
Volume	1844
Issue number	6
Early online date	16 Mar 2014
DOIs	https://doi.org/10.1016/j.bbapap.2014.03.006
Publication status	Published - Jun 2014

Keywords

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

UN SDGs

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

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10.1016/j.bbapap.2014.03.006

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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

@article{5f3f415e6dbb428790940e7deb090f59,

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.",

keywords = "Multi-target drug , Flavin adduct, Alzheimer{\textquoteright}s disease, ASS234, PF9601N, Crystal structure",

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.}",

note = "Authors thank our funding sources: COST Action CM1103 STSM10483 (GE); School of Biology at the University of St. Andrews (JA); MIUR (Italy) for PRIN09 (grant number 20098FYYZW002 to CB); and MINECO (Gobierno de Espa{\~n}a) for SAF2012-33304 (JMC and MU). This collaborative work was enabled by COST Action CM1103, Structure-based drug design for diagnosis and treatment of neurological diseases. ",

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doi = "10.1016/j.bbapap.2014.03.006",

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journal = "Biochimica et Biophysica Acta - Proteins and Proteomics",

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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

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, 06.2014, p. 1104–1110.

Research output: Contribution to journal › Article › 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.

N1 - Authors thank our funding sources: COST Action CM1103 STSM10483 (GE); School of Biology at the University of St. Andrews (JA); MIUR (Italy) for PRIN09 (grant number 20098FYYZW002 to CB); and MINECO (Gobierno de España) for SAF2012-33304 (JMC and MU). This collaborative work was enabled by COST Action CM1103, Structure-based drug design for diagnosis and treatment of neurological diseases.

PY - 2014/6

Y1 - 2014/6

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.

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.

KW - Multi-target drug

KW - Flavin adduct

KW - Alzheimer’s disease

KW - ASS234

KW - PF9601N

KW - Crystal structure

U2 - 10.1016/j.bbapap.2014.03.006

DO - 10.1016/j.bbapap.2014.03.006

M3 - Article

SN - 1570-9639

VL - 1844

SP - 1104

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 Jun;1844(6):1104–1110. Epub 2014 Mar 16. 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

Abstract

Keywords

UN SDGs

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