Alzheimer's disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds' effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD.

• Klíčová slova
• Alzheimer’s disease, N-methyl-d-aspartate receptor, acetylcholinesterase, enzyme inhibition, monoamine oxidase A/B, multi-target directed ligands,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• cholinesterasové inhibitory terapeutické užití   MeSH
• inhibitory MAO terapeutické užití   MeSH
• lidé MeSH
• monoaminoxidasa metabolismus   MeSH
• neuroblastom * farmakoterapie   MeSH
• racionální návrh léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• inhibitory MAO MeSH
• monoaminoxidasa MeSH

Huntington disease (HD) is the most frequent monogenetic neurodegenerative disease and can be unequivocally diagnosed even in the preclinical stage, at least in all individuals in whom the CAG expansion mutation in the huntingtin gene (HTT) is in the range of full penetrance. Therefore, important preconditions for an intervention early in the disease process are met, rendering modification of the course of the disease in a clinically meaningful way possible. In this respect, HD can be viewed as a model disorder for exploring neuroprotective treatment approaches. In the past emphasis was placed on the compensation of a suspected neurotransmitter deficit (GABA) analogous to Parkinson's disease and on classical neuroprotective strategies to influence hypothetical common pathways in neurodegenerative diseases (e.g., excitotoxicity, mitochondrial dysfunction, oxidative stress). With the discovery of the causative HTT mutation in 1993, therapeutic research increasingly focused on intervening as proximally as possible in the chain of pathophysiological events. Currently, an important point of intervention is the HTT mRNA with the aim of reducing the continued production of mutant huntingtin gene products and thus relieving the body of their detrimental actions. To this end, various treatment modalities (single-stranded DNA and RNA, divalent RNA and zinc finger repressor complexes, orally available splice modulators) were developed and are currently in clinical trials (phases I-III) or in late stages of preclinical development. In addition, there is the notion that it may be possible to modify the length of the somatically unstable CAG mutation, i.e. its increase in the brain during the lifetime, thereby slowing the progression of HD.

Die Huntington-Krankheit (HK) ist die häufigste monogenetische neurodegenerative Erkrankung und kann bereits im präklinischen Stadium zweifelsfrei diagnostiziert werden, zumindest in allen Fällen, bei denen die CAG-Expansionsmutation im Huntingtin-Gen (HTT) im Bereich der vollen Penetranz liegt. Wichtige Voraussetzungen für eine früh im Krankheitsprozess einsetzende und deshalb den weiteren Verlauf der Krankheit in klinisch relevanter Weise modifizierende Therapie sind damit gegeben und machen die HK zu einer Modellerkrankung für neuroprotektive Behandlungsansätze. In der Vergangenheit lag der Schwerpunkt auf dem Ausgleich vermuteter Neurotransmitterdefizite (GABA) analog zur Parkinson-Erkrankung und auf klassischen neuroprotektiven Strategien zur Beeinflussung hypothetischer gemeinsamer Endstrecken neurodegenerativer Erkrankungen (z. B. Exzitotoxizität, mitochondriale Dysfunktion, oxidativer Stress etc.). Mit der Entdeckung der krankheitsverursachenden HTT-Mutation im Jahr 1993 fokussierte sich die Therapieforschung zunehmend darauf, soweit proximal wie möglich in die pathophysiologische Ereigniskette einzugreifen. Ein wichtiger Ansatzpunkt ist hier die HTT-mRNA mit dem Ziel, die Nachproduktion mutierter Huntingtin-Genprodukte zu senken und damit den Körper von deren schädigenden Auswirkungen zu entlasten; zu diesem Zweck sind verschiedene Behandlungsmodalitäten (einzelsträngige DNA und RNA, divalente RNA und Zinkfinger-Repressorkomplexe, oral verfügbare Spleißmodulatoren) entwickelt worden, die sich in der klinischen Prüfung (Phase I–III) oder in späten Stadien der präklinischen Entwicklung befinden. Zudem zeichnet sich ab, dass es möglich sein könnte, die Länge der somatisch instabilen, d. h. über die Lebenszeit v. a. im Hirngewebe zunehmende CAG-Mutation selbst zu beeinflussen und die Progression der HK hierdurch zu bremsen.

• Klíčová slova
• Antisense oligonucleotide, Disease modification, Gene therapy, HTT mRNA, Neuroprotection,
• MeSH
• antisense oligonukleotidy MeSH
• Huntingtonova nemoc * diagnóza   farmakoterapie   genetika   MeSH
• lidé MeSH
• mozek MeSH
• mutace genetika   MeSH
• neurodegenerativní nemoci * MeSH
• protein huntingtin genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antisense oligonukleotidy MeSH
• protein huntingtin MeSH