학술논문
Evaluation of γ-carboline-phenothiazine conjugates as simultaneous NMDA receptor blockers and cholinesterase inhibitors.
Document Type
Academic Journal
Author
Schwarthoff S; Institute of Pharmacy, Pharmaceutical Biology, University of Jena, Semmelweisstrasse 10, 07743 Jena, Germany.; Tischer N; Institute of Pharmacy, Pharmaceutical Biology, University of Jena, Semmelweisstrasse 10, 07743 Jena, Germany.; Sager H; Institute of Pharmacy, Pharmaceutical Biology, University of Jena, Semmelweisstrasse 10, 07743 Jena, Germany.; Schätz B; Institute of Pharmacy, Pharmaceutical Biology, University of Jena, Semmelweisstrasse 10, 07743 Jena, Germany.; Rohrbach MM; Institute of Pharmacy, Pharmaceutical Biology, University of Jena, Semmelweisstrasse 10, 07743 Jena, Germany.; Raztsou I; Institute of Organic Chemistry and Macromolecular Chemistry, University of Jena, Humboldtstrasse 10, 07743 Jena, Germany.; Robaa D; Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, 06120 Halle/Saale, Germany.; Gaube F; Institute of Pharmacy, Pharmaceutical Biology, University of Jena, Semmelweisstrasse 10, 07743 Jena, Germany.; Arndt HD; Institute of Organic Chemistry and Macromolecular Chemistry, University of Jena, Humboldtstrasse 10, 07743 Jena, Germany.; Winckler T; Institute of Pharmacy, Pharmaceutical Biology, University of Jena, Semmelweisstrasse 10, 07743 Jena, Germany. Electronic address: t.winckler@uni-jena.de.
Source
Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE
Subject
Language
English
Abstract
Alzheimer's disease (AD) is the most common form of dementia. It is associated with the impairment of memory and other cognitive functions that are mainly caused by progressive defects in cholinergic and glutamatergic signaling in the central nervous system. Inhibitors of acetylcholinesterase (AChE) and ionotropic glutamate receptors of the N-methyl-d-aspartate (NMDA) receptor family are currently approved as AD therapeutics. We previously showed using a cell-based assay of NMDA receptor-mediated glutamate-induced excitotoxicity that bis-γ-carbolinium conjugates are useful NMDA receptor blockers. However, these compounds also act as subnanomolar AChE inhibitors, which may cause serious anticholinergic side effects when applied in vivo. Here, we evaluated new structures containing γ-carbolines linked to phenothiazine via a propionyl spacer. These compounds were superior to the previously characterized bis-γ-carbolinium conjugates because they blocked NMDA receptors without requiring a quaternary pyridine N-atom and inhibited AChE with moderate IC 50 values of 0.54-5.3 µM. In addition, these new compounds displayed considerable selectivity for the inhibition of butyrylcholinesterase (BChE; IC 50 = 0.008-0.041 µM), which may be favorable for AD treatment. Inhibitory activities towards the NMDA receptors and AChE were in the same micromolar range, which may be beneficial for equal dosing against multiple targets in AD patients.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
(Copyright © 2021 Elsevier Ltd. All rights reserved.)