Structure-Activity Relationships in the 8-Amino-6,7,8,9-tetrahydro-3H-benz[e]indole Ring System. Part 1: Effects of Substituents in the Aromatic System on Serotonin and Dopamine Receptor Subtypes

Stjernlöf, Peter; Ennis,; Lo, Hansson; Rl, Hoffman; Nb, Ghazal; Sundell, Staffan; Mw, Smith; Svensson, Kjell; Carlsson, Anita; Wikström, H.

doi:10.1021/jm00012a021

Cited by 21 publications

(5 citation statements)

References 27 publications

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“…An unsubstituted indole-NH moiety is crucial for the interaction with the 5-HT 1A receptor. The N-methyl compounds are significantly less potent [55]. Without loss in 5-HT 1A affinity one of the propyl groups can be replaced by a variety of large substituents such as glutarimide-butyl (36 -38) ( Table 4).…”

Section: -Htmentioning

confidence: 99%

Derivatives as 5HT1A Receptor Ligands-Past and Present

Caliendo¹,

Santagada²,

Perissutti³

et al. 2005

CMC

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Serotonin is a neuromediator, well-know for its implication in mood regulation, anxiety, depression and, insomnia as well as in normal human function such as sleep, sexual activity and appetite. In this way, serotonin (5-hydroxytryptamine, 5-HT) is one of the most attractive targets for medicinal chemists and pharmaceutical companies. Among 5-HTRs, the 5-HT1A subtype is the best studied, and it is generally accepted that it is involved in psychiatric disorders such as anxiety and depression. Several structurally different compounds are known to bind 5-HT1A receptor sites such as aminotetralins, ergolines, arylpiperazines, indolylalkylamines, aporphines and aryloxyalkyl-amines. In this review, we report an overview of the 5-HT1A receptor ligands, belonging to different chemical classes.

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Section: -Htmentioning

confidence: 99%

Derivatives as 5HT1A Receptor Ligands-Past and Present

Caliendo¹,

Santagada²,

Perissutti³

et al. 2005

CMC

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“…In the present study however, the CNDO point charge maxima and minima are used as a measure of similarity between ring fragments, not purely as a measure of H-bonding ability. Calculated point charges, dipoles, and molecular orbital energies have all previously been employed in generating QSAR's. ,− …”

Section: Descriptor Generation and Principal Components Analysismentioning

confidence: 99%

“…Principal components analysis (PCA) is a statistical technique which transforms a set of partially cross-correlated data into a smaller set of new, orthogonal variables called the principal components (PC's) which still retain much of the descriptive power of the original data . PCA has been applied to several series of chemical structures and fragments including α-amino acids and benzene ring substituents. , A different technique with similar aims, nonlinear mapping, has recently been used to select test series and derive structure−activity relationships for aromatic substituents and aliphatic fragments …”

Section: Introductionmentioning

confidence: 99%

Principal Components Describing Biological Activities and Molecular Diversity of Heterocyclic Aromatic Ring Fragments

Gibson¹,

McGuire²,

Rees³

1996

J. Med. Chem.

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Ten physicochemical variables have been calculated for each of 100 different aromatic rings. These variables were selected because of their potential involvement in the molecular recognition of drug-receptor binding interactions, and they include size, lipophilicity, dipole magnitude and orientation, HOMO and LUMO energies, and electronic point charges. A total of 59 different aromatic ring systems were studied including monocyclics and [5.5]-, [6.5]- and [6.6]-fused bicyclics. A principal components analysis of b1ese results generated four principal components which account for 84% of the total variance in the data. These principal components provide a quantitative measure of molecular diversity, and their relevance for structure-activity relationships is discussed. The principal components correlate with the in vitro biological activity of heterocyclic aromatic fragments within a series of previously reported HIV-1 reverse transcriptase inhibitors.

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“…Benz[ e ]indole derivatives have been shown in the past to exhibit potent agonist activity for the dopamine D 2 receptor. 35 The remaining compounds in the series were weak to inactive. Collectively, the current results show that introduction of a heterocyclic moiety in our hybrid molecules are well to modestly tolerated.…”

Section: Resultsmentioning

confidence: 99%

Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: Impact on functional activity and selectivity for dopamine D2/D3 receptors

Gopishetty

Zhang

Kharkar

et al. 2013

Bioorganic & Medicinal Chemistry

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The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the effect of derivatization of functional groups of the agonist binding moiety in compounds developed by us earlier from the hybrid template. Binding affinity (Ki) of the new compounds was measured with tritiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed in the GTPγS binding assay. In the imidazole series, compound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3 affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionalization of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from such derivatization.

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Structure-Activity Relationships in the 8-Amino-6,7,8,9-tetrahydro-3H-benz[e]indole Ring System. Part 1: Effects of Substituents in the Aromatic System on Serotonin and Dopamine Receptor Subtypes

Cited by 21 publications

References 27 publications

Derivatives as 5HT1A Receptor Ligands-Past and Present

Derivatives as 5HT1A Receptor Ligands-Past and Present

Principal Components Describing Biological Activities and Molecular Diversity of Heterocyclic Aromatic Ring Fragments

Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: Impact on functional activity and selectivity for dopamine D2/D3 receptors

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