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A therapeutic approach to cerebrovascular diseases based on indole substituted hydrazides and hydrazines able to interact with human vascular adhesion protein-1, monoamine oxidases (A and B), AChE and BuChE

  • Neurology and Preclinical Neurological Studies - Original Article
  • Published:
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Abstract

Herein, we report the biological evaluation of a series of indole substituted hydrazides and hydrazines throughout the assessment of their multipotent inhibitory potency towards monoamine oxidase (MAO) A and B, semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), and the cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Hydrazine JL72 (3-(3-hydrazinylpropyl)-1H-indole) showed a potent, reversible and non-time-dependent inhibition of MAO-A, which suggests its capacity in restoring serotoninergic neurotransmission being devoid of the side effects observed for classic MAO-A inhibitors. In addition, JL72 behaved as a moderate BuChE inhibitor. Finally, both hydrazines and hydrazides derivatives showed high affinity towards SSAO/VAP-1. Among them, JL72 behaved as a noncompetitive and the most potent inhibitor (IC50 = 0.19 ± 0.04 μM), possessing also a significant anti-inflammatory activity. The combined inhibition of SSAO/VAP-1, MAO (A and B), AChE and BuChE appear as an important therapeutic target to be considered in the treatment of cerebrovascular and neurological disorders such as Alzheimer’s disease.

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Abbreviations

Ach:

Acetylcholine

AChE:

Acetylcholinesterase

AChEI:

Acetylcholinesterase inhibitor

AD:

Alzheimer’s disease

BuChE:

Butyrylcholinesterase

CAA:

Cerebral amyloid angiopathy

DTNB:

5,5′-Dithiobis-2-nitrobenzoic acid

5-HT:

5-Hydroxytryptamine

MAO:

Monoamine oxidase

MAOI:

Monoamine oxidase inhibitor

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

MA:

Methylamine

SSAO/VAP-1:

Semicarbazide sensitive amine oxidase/vascular adhesion protein-1

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Acknowledgments

A. Samadi thanks the CSIC for I3P post-doctoral contract, J. Marco-Contelles and M. Unzeta thank the MICIN for grants: SAF2006-08764-C02-01, SAF2009-07271, SAF2012-33304, and (COST, EU) Action CM-1103 for support.

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Authors and Affiliations

  1. Departament de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain

    Gerard Esteban, Irene Bolea, Ping Sun, Montse Solé & Mercedes Unzeta

  2. Laboratorio de Química Médica (IQOG, CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain

    Abdelouahid Samadi & José Marco-Contelles

Authors
  1. Gerard Esteban
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  2. Irene Bolea
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  3. Ping Sun
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  4. Montse Solé
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  5. Abdelouahid Samadi
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  6. José Marco-Contelles
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  7. Mercedes Unzeta
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Corresponding author

Correspondence to Mercedes Unzeta.

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This manuscript is dedicated to the memory of Dr. Eldiberto M. Fernández-Álvarez (1928–1996).

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Esteban, G., Bolea, I., Sun, P. et al. A therapeutic approach to cerebrovascular diseases based on indole substituted hydrazides and hydrazines able to interact with human vascular adhesion protein-1, monoamine oxidases (A and B), AChE and BuChE. J Neural Transm 120, 911–918 (2013). https://doi.org/10.1007/s00702-012-0949-x

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  • DOI: https://doi.org/10.1007/s00702-012-0949-x

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