Octoclothepin enantiomers. A reinvestigation of their biochemical and pharmacological activity in relation to a new receptor-interaction model for dopamine D-2 receptor antagonists

Boegesoe, K. P.; Liljefors, Tommy; J, Arnt; Hyttel, John; Pedersen, Henrik

doi:10.1021/jm00111a015

Cited by 28 publications

(12 citation statements)

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“…Recently, the model was further supported by a study of both enantiomers of octoclothepin. 11 The model has been used to rationalize the affinity for D2 receptors for compounds from different chemical classes such as dexclamol,10 butaclamol,12 benzamides,13 thioxanthenes,14 phenothiazines,14 cyproheptadine derivatives,15 and tetracyclic spiroamines. 15 Recently, it was shown that phenylindans, -indenes, and -indoles with high affinity for D2 receptors can also be well accommodated into the model.…”

Section: Introductionmentioning

confidence: 99%

Development of a Receptor-Interaction Model for Serotonin 5-HT2 Receptor Antagonists. Predicting Selectivity with Respect to Dopamine D2 Receptors

Andersen¹,

Liljefors²,

Gundertofte³

et al. 1994

J. Med. Chem.

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A receptor-interaction model for serotonin 5-HT2 receptor antagonists has been developed by conformational analysis with molecular mechanics (MM2(91)) and superimposition studies of serotonin 5-HT2 receptor antagonists. Substituted 3-(4-piperidinyl)-,1-(4- piperidinyl)-,3-(1,2,3,6-tetrahydropyridin-4-yl)-, and 1-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles, substituted 3-(4-fluorophenyl)-1-(4-piperazinyl)indans, cyprohepatadine derivatives, ritanserin, and danitracene have been used as bases for the model. Other serotonin 5-HT2 receptor antagonists, such as ketanserin and MDL 11,939, are well accommodated into the model. Comparison of the model with a recently described receptor-interaction model for dopamine D2 receptor antagonists suggests a common pharmacophore for dopamine D2 and serotonin 5-HT2 receptor antagonists. Important steric differences between 5-HT2 receptor antagonists with additional high affinity for dopamine D2 receptors and serotonin 5-HT2 receptor antagonists with high selectivity versus D2 receptors are described. The geometry of the receptor-interaction model described is significantly different from that of a recently reported receptor-interaction model for 5-HT2 receptor agonists and antagonists developed by use of (+)-LSD as a template, suggesting the existence of two binding modes at the 5-HT2 receptor.

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Section: Introductionmentioning

confidence: 99%

Development of a Receptor-Interaction Model for Serotonin 5-HT2 Receptor Antagonists. Predicting Selectivity with Respect to Dopamine D2 Receptors

Andersen¹,

Liljefors²,

Gundertofte³

et al. 1994

J. Med. Chem.

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“…by inhibiting JAK kinases 20 . Octoclothepine inhibits GPCRs that elevate intracellular cAMP levels 21 , and cAMP impairs survival of BCR-Abl-expressing cells (see below).…”

Section: Resultsmentioning

confidence: 99%

A cell competition-based drug screen identifies a novel compound that induces dual c-Myc depletion and p53 activation

Tadele

Robertson

Crispin

et al. 2020

Preprint

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BCR-Abl is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells. Leukemic stem cells are cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. Using BCR-Abl as a model oncogene, we performed a drug screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells, and identified several compounds that selectively target BCR-Abl-transformed cells. Systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. c-Myc depletion occurred in a wide range of tumor types, including leukemia, lymphoma, lung, glioblastoma and breast cancer. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest and cell differentiation, and primary leukemic stem cells were particularly sensitive to DJ34. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against leukemic stem cells.

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“…An early study of ( S )‐ 14 (Fig. 7), neuroleptic compound that binds on dopamine D‐2 receptor [30], has revealed that stable conformation of ( S )‐ 14 , which is responsible for the dopamine D‐2 receptor antagonism, is significantly different from the one observed in the crystal [31].…”

Section: Resultsmentioning

confidence: 99%

Novel tetracyclic imidazole derivatives: Synthesis, dynamic NMR study, and anti‐inflammatory evaluation

Rupčić

Modrić

Hutinec

et al. 2010

Journal of Heterocyclic Chem

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A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route starting from the known tricyclic diketones 2a-2d. Intermediary dibenzooxepin [4,5-d]imidazoles (3a, 3c) and dibenzothiepin [4,5-d]imidazoles (3b, 3d) are N-protected to 4e, 4f and to the isomeric compounds 5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formylated at C(2) to afford 7a-7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets of isomeric x-dimethylaminoalkyl derivatives 9a-9v. N-deprotection of 9i-9v led to the compounds 10a-10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESY NMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied by dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be $11.5 and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their antiinflammatory activity.

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Octoclothepin enantiomers. A reinvestigation of their biochemical and pharmacological activity in relation to a new receptor-interaction model for dopamine D-2 receptor antagonists

Cited by 28 publications

References 1 publication

Development of a Receptor-Interaction Model for Serotonin 5-HT2 Receptor Antagonists. Predicting Selectivity with Respect to Dopamine D2 Receptors

Development of a Receptor-Interaction Model for Serotonin 5-HT2 Receptor Antagonists. Predicting Selectivity with Respect to Dopamine D2 Receptors

A cell competition-based drug screen identifies a novel compound that induces dual c-Myc depletion and p53 activation

Novel tetracyclic imidazole derivatives: Synthesis, dynamic NMR study, and anti‐inflammatory evaluation

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