Ringerweiterung, Hydoxylierung und Methoxylierung: Neues zu Struktur-Wirkungsbeziehungen an Dopamin Rezeptor Liganden vom Dibenz- und Benzindoloazecin Typ

Die Klasse der Azecine stellt eine neuartige Gruppe von Dopamin Rezeptor Antagonisten dar, deren Affinitätsprofil durch eine Selektivität zur D1 Familie gekennzeichnet ist. Die vorliegende Arbeit setzte sich zum Ziel, durch strukturelle Modifikationen zweier Leitverbindungen - LE 300 und LE 404 -, die Kenntnisse über Struktur-Wirkungsbeziehungen in dieser Stoffklasse zu erweitern und möglicherweise Affinitäts- und Selektivitätssteigerungen zu erzielen. Untersucht wurden der Einfluss einer Erweiterung des zentralen Zehnringes zum Elf-und Zwölfring auf die biologische Aktivität, wie auch die affinitätsmodulierenden Eigenschaften unterschiedlicher Substituenten an den aromatischen Ringen der Dibenzo- und Benzindoloderivate. Dazu wurden in bis zu 16-stufigen Synthesen 24 neue Zielverbindungen hergestellt, 6 davon sind Derivate bisher nicht beschriebener heterocyclischer Ringgerüste. Die Affinitäten der Substanzen wurden durch Radioligandbindungsstudien an allen humanen, geklonten Dopamin Rezeptoren (D1-D5) gemessen, ihre Funktionalität an einer hinreichenden Auswahl von Rezeptoren (D1, D2 und D5)mit Hilfe eines Calcium Assays bestimmt. Die neuen Verbindungen sind Antagonisten oder inverse Agonisten an den Dopamin Rezeptoren und die Affinitäten (Ki-Werte) der meisten liegen zum Teil im nanomolaren bis subnanomolaren Bereich

9-Methyl-β-carboline inhibits monoamine oxidase activity and stimulates the expression of neurotrophic factors by astrocytes

β-Carbolines (BC) are pyridoindoles, which can be found in various exogenous and endogenous sources. Recent studies revealed neurostimulative, neuroprotective, neuroregenerative and anti-inflammatory effects of 9-methyl-BC (9-Me-BC). Additionally, 9-me-BC increased neurite outgrowth of dopaminergic neurons independent of dopamine uptake into these neurons. In this study, the role of astrocytes in neurostimulative, neuroregenerative and neuroprotective properties of 9-me-BC was further explored.9-Me-BC exerted anti-proliferative effects without toxic properties in dopaminergic midbrain and cortical astrocyte cultures. The organic cation transporter (OCT) but not the dopamine transporter seem to mediate at least part the effect of 9-me-BC on astrocytes. Remarkably, 9-me-BC stimulated the gene expression of several important neurotrophic factors for dopaminergic neurons like Artn, Bdnf, Egln1, Tgfb2 and Ncam1. These factors are well known to stimulate neurite outgrowth and to show neuroprotective and neuroregenerative properties to dopaminergic neurons against various toxins. Further, we show that effect of 9-me-BC is mediated through phosphatidylinositol 3-kinase (PI3K) pathway. Additionally, 9-me-BC showed inhibitory properties to monoamine oxidase (MAO) activity with an IC50 value of 1 µM for MAO-A and of 15.5 µM for MAO-B. The inhibition of MAO by 9-me-BC might contribute to the observed increased dopamine content and anti-apoptotic properties in cell culture after 9-me-BC treatment in recent studies. Thus, 9-me-BC have a plethora of beneficial effects on dopaminergic neurons warranting its exploration as a new multimodal anti-parkinsonian medication

Evaluation of Homobivalent Carbolines as Designed Multiple Ligands for the Treatment of Neurodegenerative Disorders

Neurodegenerative diseases represent a challenge for biomedical research due to their high prevalence and lack of mechanism-based treatments. Because of the complex pathology of neurodegenerative disorders, multifunctional drugs have been increasingly recognized as potential treatments. We identified homobivalent γ-carbolinium salts as potent inihitors of both cholinesterases, <i>N</i>-methyl-d-aspartate receptors, and monoamine oxidases. Homobivalent γ-carbolines displayed similar structure–activity relationships on all tested targets and may present promising designed multiple ligands for the treatment of neurodegenerative disorders

Small molecules intercept Notch signaling and the early secretory pathway

Notch signaling has a pivotal role in numerous cell-fate decisions, and its aberrant activity leads to developmental disorders and cancer. To identify molecules that influence Notch signaling, we screened nearly 17,000 compounds using automated microscopy to monitor the trafficking and processing of a ligand-independent Notch–enhanced GFP (eGFP) reporter. Characterization of hits in vitro by biochemical and cellular assays and in vivo using zebrafish led to five validated compounds, four of which induced accumulation of the reporter at the plasma membrane by inhibiting γ-secretase. One compound, the dihydropyridine FLI-06, disrupted the Golgi apparatus in a manner distinct from that of brefeldin A and golgicide A. FLI-06 inhibited general secretion at a step before exit from the endoplasmic reticulum (ER), which was accompanied by a tubule-to-sheet morphological transition of the ER, rendering FLI-06 the first small molecule acting at such an early stage in secretory traffic. These data highlight the power of phenotypic screening to enable investigations of central cellular signaling pathways