Residues at the Indole‐<i>NH</i> of LE300 Modulate Affinities and Selectivities for Dopamine Receptors

Robaa, Dina; Kretschmer, Robert; Siol, Oliver; AbulAzm, Shams ElDin; ElKhawass, ElSayeda; Lehmann, Jochen; Enzensperger, Christoph

doi:10.1002/ardp.201000121

Cited by 14 publications

(10 citation statements)

References 18 publications

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“…Best results, but with no signifi cance were observed for D 2 /locomotor activity (r 2 = 0.71, p = 0.22), D 4 /CAR-inhibition (r 2 = 0.63, p = 0.59) and D 2 /catalepsy (r 2 = 0.64, p = 0. 16). Surprisingly there was a strong and significant correlation between the CAT(C-L)/CAR ratio and D 1 (r 2 = 0.95, p = 0.03) or D 5 receptors (r 2 = 0.96, p = 0.03), which could imply an advantage of high affi nities to the D 1 receptor family, displayed by almost all hexahydrodibenz-and -benzindoloazecines.…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

Molecular Combination of the Dopamine and Serotonin Scaffolds Yield in Novel Antipsychotic Drug Candidates - Characterization by in vivo Experiments

Schulze

Siol

Robaa

et al. 2012

Arzneimittelforschung

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Serotonin and dopamine play an important role in the aetiology of schizophrenia. Combination of the structural scaffolds of both neurotransmitters in a single molecule lead to aromatic [d,g]-bisannelated azecine derivatives, which have been shown to be nanomolar to subnanomolar dopamine D1-D5 receptor antagonists with a preference for the D1 family. In this work the potential antipsychotic activity of some azecine derivatives was predicted by their dopamine receptor affinities obtained in vitro from radioligand binding experiments and conclusively confirmed in vivo (rats) by applying a conditioned avoidance model. Furthermore, the compounds were tested in vivo for the development of catalepsy, which is a predictive parameter for extra-pyramidal side-effects caused by many antipsychotics. The investigated azecines displayed low cytotoxicity, and the affinities for human dopamine D1-D5 and serotonin 5-HT2 A receptors were in a nanomolar range. In vivo, their antipsychotic activities in the rat model were comparable with those of haloperidol and risperidone, but revealed a 2-5 times better therapeutic range with regard to catalepsy. Preliminary tests for oral bioavailability also revealed promising results for this new class of potential antipsychotic compounds. In conclusion, our in vivo experiments show that aromatic [d,g]-annelated azecines represent a novel and advantageous class of potential atypical neuroleptics.

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Section: Discussionmentioning

confidence: 86%

“…is a new compound, prepared from 5,6,8,9,14,14b-hexahydroindolo[2',3',3,4]pyrido[2,1-a]isoquinoline [ 16 ] .…”

Section: Substancesmentioning

confidence: 99%

Molecular Combination of the Dopamine and Serotonin Scaffolds Yield in Novel Antipsychotic Drug Candidates - Characterization by in vivo Experiments

Schulze

Siol

Robaa

et al. 2012

Arzneimittelforschung

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“…313 Similar procedures have been applied to generate a wide range of potent dopamine antagonists. [314][315][316][317] Ring expansion likewise has proven applicable for some macrocycles, but is also restricted in scope. For example, construction of the scaffold for the (208) and related analogues was achieved utilizing two successive one atom ring expansions from cyclooctanone.…”

Section: Ring Expansion/openingmentioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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“…The affinity of piperazinylpropylindole derivatives for both the 5‐HT transporter (SERT) and the 5‐HT 1A receptor was recently described . In addition, linear indole‐derived alkaloids exerting neurotrophin‐like properties on primary dopaminergic neurons and the azecine‐type dopamine receptor antagonists represent a novel classes of ligands for the aforementioned targets. Multifunctional agents for Alzheimer's disease (AD) within the indole ring‐containing berberine conjugates exhibited reasonable AChE/BuChE inhibiting activity .…”

Section: Introductionmentioning

confidence: 99%

G protein‐coupled receptor binding and pharmacological evaluation of indole‐derived thiourea compounds

Szulczyk

Bielenica

Kędzierska

et al. 2019

Archiv der Pharmazie

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Four 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with the corresponding aryl/alkylisothiocyanates in a medium-polarity solvent. Their structures were confirmed by spectral techniques, and the molecular structure of 3 was determined by X-ray crystal analysis. For all derivatives, the binding affinities at the 5-HT 2A and 5-HT 2C receptors, as well as their functional activities at the 5-HT 1A and D 2 receptors, were determined. The arylthioureas 1 and 4 were the most active at the 5-HT 1A receptor, showing, at the same time, significant selectivity over the studied 5-HT 2 and D 2 receptor subtypes.The compounds were tested for their pharmacological activities within the central nervous system in relevant mouse models. The involvement of the serotonergic system in the activity of 1 and 4 was indicated. The antinociceptive action of 4 was linked to its anti-inflammatory activity. K E Y W O R D Sdopamine receptors, inverse agonists, serotonin antagonism, substituent effect

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Residues at the Indole‐NH of LE300 Modulate Affinities and Selectivities for Dopamine Receptors

Cited by 14 publications

References 18 publications

Molecular Combination of the Dopamine and Serotonin Scaffolds Yield in Novel Antipsychotic Drug Candidates - Characterization by in vivo Experiments

Molecular Combination of the Dopamine and Serotonin Scaffolds Yield in Novel Antipsychotic Drug Candidates - Characterization by in vivo Experiments

The Synthesis of Macrocycles for Drug Discovery

G protein‐coupled receptor binding and pharmacological evaluation of indole‐derived thiourea compounds

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