Skip to content

Research at St Andrews

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-reviewArticle

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

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

    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. 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-reviewReview article

  2. 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-reviewArticle

  3. 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-reviewReview article

  4. Comparative analysis of the neurochemical profile and MAO inhibition properties of N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

    De Deurwaerdère, P., Binda, C., Corne, R., Leone, C., Valeri, A., Valoti, M., Ramsay, R. R., Fall, Y. & Marco-Contelles, J. 17 May 2017 In : ACS Chemical Neuroscience. 8, 5, p. 1026-1035 10 p., cn-2016-00377h

    Research output: Research - peer-reviewArticle

  5. Neurobiology and neuropharmacology of monoaminergic systems

    Deurwaerdère, P., Ramsay, R. R. & Di Giovanni, G. Apr 2017 In : Progress in Neurobiology. 151, p. 1-3 3 p., PRONEU 1480

    Research output: Research - peer-reviewEditorial

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-reviewArticle

  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-reviewArticle

  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-reviewArticle

  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-reviewArticle

ID: 110641349