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

54 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 (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	7
Journal	Biochimica et Biophysica Acta - Proteins and Proteomics
Volume	1844
Issue number	6
DOIs	https://doi.org/10.1016/j.bbapap.2014.03.006
Publication status	Published - Jun 2014
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Analytical Chemistry
Biophysics
Biochemistry
Molecular Biology

UN SDGs

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

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10.1016/j.bbapap.2014.03.006

Cite this

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

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

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

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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.",

keywords = "ASS234, Alzheimer's disease, 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.\}",

note = "Funding Information: We 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. For the whole protein mass determinations, we thank Dr Catherine Botting, the BSRC mass spectrometry facility at the University of St Andrews, and the Wellcome Trust for instrument funding. ",

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AU - Unzeta, Mercedes

AU - Marco-Contelles, José

AU - Binda, Claudia

AU - Ramsay, Rona R.

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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

ASJC Scopus subject areas

UN SDGs

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