Dopamine/Serotonin Receptor Ligands. 10: SAR Studies on Azecine-type Dopamine Receptor Ligands by Functional Screening at Human Cloned D1, D2L, and D5 Receptors with a Microplate Reader Based Calcium Assay Lead to a Novel Potent D1/D5 Selective Antagonist

Hoefgen, Barbara; Decker, Michael; Mohr, Patrick; Schramm, Astrid M; Rostom, Sherif A. F.; El‐Subbagh, Hussein I.; Schweikert, Peter M.; Rudolf, Dirk R; Kassack, Matthias U.; Lehmann, Jochen

doi:10.1021/jm050846j

Cited by 78 publications

(79 citation statements)

References 17 publications

(40 reference statements)

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“…), which exhibits the highest structural resemblance to dopamine, the natural ligand, showed ca. 100 -1000-fold lower affinities than the monohydroxylated LE404 1 [3].…”

mentioning

confidence: 89%

A Novel Non‐phenolic Dibenzazecine Derivative with Nanomolar Affinities for Dopamine Receptors

Robaa

AbulAzm

Lehmann

et al. 2011

Chemistry & Biodiversity

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Dibenzazecines are a novel class of dopamine receptor antagonists, characterized by their high affinities as well as their tendency for D(1) selectivity. Hitherto, the most active dibenzazecines were phenolic in nature; a 3-OH substituent was found to result in the highest affinities. However, the phenolic nature of these compounds mostly renders them unsuitable for in vivo application, due to the poor pharmacokinetic profile, imparted by the phenolic group. A novel dibenzazecine derivative was prepared, with methylenedioxy moiety, connecting C(2) amd C(3), instead of the 3-OH group. The newly synthesized derivative 3 showed high affinities similar to the lead LE404, displaying nanomolar affinities for all dopamine receptor subtypes. Its dibrominated derivative 4, though exhibiting almost a fivefold decrease in affinities, still displayed nanomolar ones for all dopamine receptors, except for D(4) . In a functional Ca(2+) assay, both compounds 3 and 4 were found to possess antagonistic properties towards the dopamine receptors.

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“…), which exhibits the highest structural resemblance to dopamine, the natural ligand, showed ca. 100 -1000-fold lower affinities than the monohydroxylated LE404 1 [3].…”

mentioning

confidence: 89%

A Novel Non‐phenolic Dibenzazecine Derivative with Nanomolar Affinities for Dopamine Receptors

Robaa

AbulAzm

Lehmann

et al. 2011

Chemistry & Biodiversity

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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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“…Haloperidol (Sigma-Aldrich, Germany), Risperidone (Promochem, Germany), LE404 (7-methyl-5,6,7,8,9,14-hexahydrodibenzo [ d,g ]azecine-3-ol) [ 15 ] , LE425 (3-methoxy-7-methyl-5,6,7,8,9,14-hexahydrodibenzo[ d,g ]azecine) [ 15 ] , LE300 (7-methyl-6,7,8,9,14,15- [ 10 ] were available in the lab from previous work. LE300ME (7,7,8,9,14,…”

Section: Substancesmentioning

confidence: 99%

“…Locomotor activity a data taken from Hoefgen et al [ 15 ] ; b data taken from Mohr et al [ 12 ] ; c data taken from Kassack et al [ 11 ] ; d data taken from Enzensberger et al [ 27 ] ; e data from PDSP database [ 28 ] …”

Section: In Vivo Testsmentioning

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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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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Dopamine/Serotonin Receptor Ligands. 10: SAR Studies on Azecine-type Dopamine Receptor Ligands by Functional Screening at Human Cloned D₁, D_2L, and D₅ Receptors with a Microplate Reader Based Calcium Assay Lead to a Novel Potent D₁/D₅ Selective Antagonist

Cited by 78 publications

References 17 publications

A Novel Non‐phenolic Dibenzazecine Derivative with Nanomolar Affinities for Dopamine Receptors

A Novel Non‐phenolic Dibenzazecine Derivative with Nanomolar Affinities for Dopamine Receptors

The Synthesis of Macrocycles for Drug Discovery

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

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