Main author: Sebastian Oddsson
Institution or Company: Faculty of Pharmaceutical Sciences, University of Iceland
Co-Authors, Institution or Company:
Natalia M. Kowal, 1 Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland 2 Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney 3 Brain and Mind Centre, The University of Sydney. Philip K. Ahring, 2 Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney 3 Brain and Mind Centre, The University of Sydney. Elin S. Olafsdottir, 1 Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland. Thomas Balle, 2 Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney 3 Brain and Mind Centre, The University of Sydney.
Introduction: Despite extensive efforts in the development of drugs for complex neurodegenerative diseases, treatment remains challenging or ineffective, and new treatment strategies are necessary. One approach is the design of multi-target drugs, which can potentially address the complex nature of disorders such as Alzheimer’s disease.
Methods: Using computational chemistry methods, parallel and independent screening of a virtual compound library from the ZINC15 database against acetylcholinesterase (AChE) and α7 nicotinic acetylcholine receptor (α7 nAChR) that potentially possess activity at both two protein targets. Based on ligand efficiency as well as scaffold and molecular diversity putative dual-ligands were selected for in vitro validation by Ellman’s method and two-electrode voltage-clamp electrophysiology.
Results: Virtual screening of 3,848,234 drug-like and commercially available molecules resulted in an intersecting set of 57 compounds, 16 of which were then purchased for in vitro validation. One of the identified hits identified, N,N-dimethyl-1-(4-(3-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-6-yl)phenyl)ethan-1-amine (Ýmir-2), has dual-activity as an AChE inhibitor and as an α7 nAChR agonist. Ýmir-2 was shown to exhibit the desired activity profile (AChE IC50 = 2.58 ± 0.96 µM; α7 nAChR activation = 7.0 ± 0.9% at 200 µM).
Conclusions: We report the first compound acting both as α7 nAChR agonist and AChE inhibitor. Compounds with this activity profile could serve as new drug leads for the treatment of Alzheimer’s disease.
