- N-SUBSTITUTED INDOLES AND OTHER HETEROCYCLES FOR TREATING BRAIN DISORDERS
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The present invention provides N-substituted indoles and other heterocycles and methods of using the compounds for treating brain disorders.
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Paragraph 0189; 0192; 0216
(2020/09/12)
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- Identification of Psychoplastogenic N, N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies
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Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens possess enormous potential as neurotherapeutics due to their ability to potently promote neuronal growth. Here, we report the first-ever structure-Activity relationship study with the explicit goal of identifying novel psychoplastogens. We have discovered several key features of the psychoplastogenic pharmacophore and used this information to develop N,N-dimethylaminoisotryptamine (isoDMT) psychoplastogens that are easier to synthesize, have improved physicochemical properties, and possess reduced hallucinogenic potential as compared to their DMT counterparts.
- Dunlap, Lee E.,Azinfar, Arya,Ly, Calvin,Cameron, Lindsay P.,Viswanathan, Jayashri,Tombari, Robert J.,Myers-Turnbull, Douglas,Taylor, Jack C.,Grodzki, Ana Cristina,Lein, Pamela J.,Kokel, David,Olson, David E.
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p. 1142 - 1155
(2020/03/10)
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- NB 06: From a simple lysosomotropic aSMase inhibitor to tools for elucidating the role of lysosomes in signaling apoptosis and LPS-induced inflammation
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Ceramide generation is involved in signal transduction of cellular stress response, in particular during stress-induced apoptosis in response to stimuli such as minimally modified Low-density lipoproteins, TNFalpha and exogenous C6-ceramide. In this paper we describe 48 diverse synthetic products and evaluate their lysosomotropic and acid sphingomyelinase inhibiting activities in macrophages. A stimuli-induced increase of C16-ceramide in macrophages can be almost completely suppressed by representative compound NB 06 providing an effective protection of macrophages against apoptosis. Compounds like NB 06 thus offer highly interesting fields of application besides prevention of apoptosis of macrophages in atherosclerotic plaques in vessel walls. Most importantly, they can be used for blocking pH-dependent lysosomal processes and enzymes in general as well as for analyzing lysosomal dependent cellular signaling. Modulation of gene expression of several prominent inflammatory messengers IL1B, IL6, IL23A, CCL4 and CCL20 further indicate potentially beneficial effects in the field of (systemic) infections involving bacterial endotoxins like LPS or infections with influenza A virus.
- Blaess, Markus,Bibak, Nelly,Claus, Ralf A.,Kohl, Matthias,Bonaterra, Gabriel A.,Kinscherf, Ralf,Laufer, Stefan,Deigner, Hans-Peter
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supporting information
p. 73 - 104
(2017/10/17)
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- Inhibition of dynamin mediated endocytosis by the Dynoles - Synthesis and functional activity of a family of indoles
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Screening identified two bisindolylmaleimides as 100 μM inhibitors of the GTPase activity of dynamin I. Focused library approaches allowed development of indole-based dynamin inhibitors called dynoles. 100-Fold in vitro enhancement of potency was noted with the best inhibitor, 2-cyano-3-(1-(2- (dimethylamino)ethyl)-1H-indol-3-yl)-N-octylacrylamide (dynole 34-2), a 1.3 ± 0.3 μM dynamin I inhibitor. Dynole 34-2 potently inhibited receptor mediated endocytosis (RME) internalization of Texas red-transferrin. The rank order of potency for a variety of dynole analogues on RME in U2OS cells matched their rank order for dynamin inhibition, suggesting that the mechanism of inhibition is via dynamin. Dynoles are the most active dynamin I inhibitors reported for in vitro or RME evaluations. Dynole 34-2 is 15-fold more active than dynasore against dynamin I and 6-fold more active against dynamin mediated RME (IC50 ～15 μM; RME IC50 ～80 μM). The dynoles represent a new series of tools to better probe endocytosis and dynamin-mediated trafficking events in a variety of cells.
- Hill, Timothy A.,Gordon, Christopher P.,McGeachie, Andrew B.,Venn-Brown, Barbara,Odell, Luke R.,Chau, Ngoc,Quan, Annie,Mariana, Anna,Sakoff, Jennette A.,Chircop, Megan,Robinson, Phillip J.,McCluskey, Adam
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experimental part
p. 3762 - 3773
(2010/04/24)
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