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Eur J Med Chem. 2014 Feb 12;73:56-72. doi: 10.1016/j.ejmech.2013.11.026. Epub 2013 Dec 7.

Cannabinoid agonists showing BuChE inhibition as potential therapeutic agents for Alzheimer's disease.

Author information

1
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
2
Departamento de Farmacología y Nutrición - Unidad Asociada al IQM (CSIC), Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. Atenas s/n, 28922 Alcorcón, Spain.
3
Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universidad Complutense, 28040 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Universidad Complutense, 28040 Madrid, Spain; CEI-Moncloa UCM - UPM, Universidad Complutense, 28040 Madrid, Spain.
4
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: juan@suricata.iqm.csic.es.

Abstract

Designing drugs with a specific multi-target profile is a promising approach against multifactorial illnesses as Alzheimer's disease. In this work, new indazole ethers that possess dual activity as both cannabinoid agonists CB2 and inhibitors of BuChE have been designed by computational methods. On the basis of this knowledge, the synthesis, pharmacological evaluation and docking studies of a new class of indazoles has been performed. Pharmacological evaluation includes radioligand binding assays with [(3)H]-CP55940 for CB1R and CB2R and functional activity for cannabinoid receptors on isolated tissue. Additionally, in vitro inhibitory assays of AChE/BuChE and the corresponding competition studies have been carried out. The results of pharmacological tests have revealed that three of these derivatives behave as CB2 cannabinoid agonists and simultaneously show BuChE inhibition. In particular, compounds 3 and 24 have emerged as promising candidates as novel cannabinoids that inhibit BuChE by a non-competitive or mixed mechanism, respectively. On the other hand, both molecules show antioxidant properties.

KEYWORDS:

Alzheimer's disease; Antioxidant; BuChE inhibitor; CB2R agonist; Drug design; Indazole ether; Multitarget drug

PMID:
24378710
DOI:
10.1016/j.ejmech.2013.11.026
[Indexed for MEDLINE]
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