Skip to content

Research at St Andrews

University > Research portal > Research publications > Kinetic and structural analysis of the irreversible inhibiti...

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

Research output: Research - peer-review › Article

DOI

Author(s)

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

School/Research organisations

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.
Close
More...

Details

Original languageEnglish
Pages (from-to)1104–1110
Number of pages6
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1844
Issue number6
Early online date16 Mar 2014
DOIs
StatePublished - Jun 2014
Additional links

    Research areas

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

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Evidence for a cyanine link between propargylamine drugs and monoamine oxidase clarifies the inactivation mechanism

    Albreht, A., Vovk, I., Mavri, J., Marco-Contelles, J. & Ramsay, R. R. 27 Apr 2018 (Accepted/In press) In : Frontiers in Chemistry. In press

    Research output: Research - peer-review › Article

  2. Kinetics, mechanism and inhibition of monoamine oxidase

    Ramsay, R. R. & Albreht, A. 7 Mar 2018 In : Journal of Neural Transmission. First Online, JONT1800019

    Research output: Research - peer-review › Review article

  3. A perspective on multi-target drug discovery and design for complex diseases

    Ramsay, R. R., Popovic-Nikolicb, M. R., Nikolic, K., Uliassi, E. & Bolognesi, M. L. 17 Jan 2018 In : Clinical and Translational Medicine. 7, 14 p., 3

    Research output: Research - peer-review › Review article

  4. Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases

    Bautista-Aguilera, Ó. M. , Hagenow, S. , Palomino-Antolin, A. , Farré-Alins, V. , Ismaili, L. , Joffrin, P-L. , Jimeno, M. L. , Soukup, O. , Janočková, J. , Kalinowsky, L. , Proschak, E. , Iriepa, I. , Moraleda, I. , Schwed, J. S. , Romero Martínez, A. , López-Muñoz, F. , Chioua, M. , Egea, J. , Ramsay, R. R. , Marco-Contelles, J. & 1 others Stark, H. 2 Oct 2017 In : Angewandte Chemie International Edition. 56, 41, p. 12765–12769 5 p., 201706072R2

    Research output: Research - peer-review › Article

  5. Assessment of enzyme inhibition: a review with examples from the development of monoamine oxidase and cholinesterase inhibitory drugs

    Ramsay, R. R. & Tipton, K. F. Jul 2017 In : Molecules. 22, 7, 46 p., 1192

    Research output: Research - peer-review › Review article

Related by journal

  1. Exploring the structural basis of the selective inhibition of monoamine oxidase A by dicarbonitrile aminoheterocycles: Role of Asn181 and Ile335 validated by spectroscopic and computational studies

    Juárez-Jiménez, J., Mendes, E., Galdeano, C., Martins, C., Silva, D. B., Marco-Contelles, J., Do Carmo Carreiras, M., Luque, F. J. & Ramsay, R. R. 1 Feb 2014 In : Biochimica et Biophysica Acta - Proteins and Proteomics. 1844, 2, p. 389-397 9 p.

    Research output: Research - peer-review › Article

  2. Hemocyanin conformational changes associated with SDS-induced phenol oxidase activation

    Baird, S., Kelly, S. M., Price, N. C., Jaenicke, E., Meesters, C., Nillius, D., Decker, H. & Nairn, J. Nov 2007 In : Biochimica et Biophysica Acta - Proteins and Proteomics. 1774, 11, p. 1380-1394 15 p.

    Research output: Research - peer-review › Article

  3. Probing the substrate specificities of human PHOSPHO1 and PHOSPHO2

    Roberts, S. J., Stewart, A. J., Schmid, R., Blindauer, C. A., Bond, S. R., Sadler, P. J. & Farquharson, C. 31 Aug 2005 In : Biochimica et Biophysica Acta - Proteins and Proteomics. 1752, 1, p. 73-82 10 p.

    Research output: Research - peer-review › Article

  4. Inhibitors alter the spectrum and redox properties of monoamine oxidase A

    Ramsay, R. R. & Hunter, D. B. J. 16 Dec 2002 In : Biochimica et Biophysica Acta - Proteins and Proteomics. 1601, 2, p. 178-184 7 p.

    Research output: Research - peer-review › Article

ID: 110641349