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BioAssay: AID 150851

Binding affinity determined against Opioid receptor mu 1 from human cloned receptor

The synthesis and biological evaluation of a series of new derivatives of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), are reported. Chemical and pharmacological studies on compounds 6 have been pursued with the aim of expanding the SAR data and validating the previously proposed model of interaction of this class of compounds with the kappa-opioid receptor. more ..
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 Tested Compounds
 Tested Compounds
All(12)
 
 
Active(11)
 
 
Unspecified(1)
 
 
 Tested Substances
 Tested Substances
All(12)
 
 
Active(11)
 
 
Unspecified(1)
 
 
 Related BioAssays
 Related BioAssays
AID: 150851
Data Source: ChEMBL (148098)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-05-24
Modify Date: 2014-08-24

Data Table ( Complete ):           View Active Data    View All Data
BioActive Compounds: 11
Description:
Title: Synthesis, biological evaluation, and receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as kappa-opioid receptor agonists endowed with antinociceptive and antiamnesic activity.

Abstract: The synthesis and biological evaluation of a series of new derivatives of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), are reported. Chemical and pharmacological studies on compounds 6 have been pursued with the aim of expanding the SAR data and validating the previously proposed model of interaction of this class of compounds with the kappa-opioid receptor. The synthesis of the previously described compounds 6 has been reinvestigated in order to obtain a more direct synthetic procedure. To study the relationship between the stereochemistry and the receptor binding affinity, compounds 6e and 6k were selected on the basis of their evident structural resemblance to tifluadom. Since a different specificity of action could be expected for the enantiomers of 6e and 6k, owing to the results shown by (S)- and (R)-tifluadom, their racemic mixtures have been resolved by means of liquid chromatography with chiral stationary phases (CSP), and the absolute configuration of the enantiomers has been studied by circular dichroism (CD) and (1)H NMR techniques. Moreover, some new 2-[(acylamino)ethyl]-1,4-benzodiazepine derivatives, 6a-d,f,g,j, have been synthesized, while the whole series (6a-o) has been tested for its potential affinity toward human cloned kappa-opioid receptor. The most impressive result obtained from the binding studies lies in the fact that this series of 2-[2-(acylamino)ethyl]-1,4-benzodiazepine derivatives binds the human cloned kappa-opioid receptor subtype very tightly. Indeed, almost all the ligands within this class show subnanomolar K(i) values, and the least potent compound 6o shows, in any case, an affinity in the nanomolar range. A comparison of the affinities obtained in human cloned kappa-receptor with the correspondent one obtained in native guinea pig kappa-receptor suggests that the human cloned kappa-receptor is less effective in discriminating the substitution pattern than the native guinea pig kappa-receptor. Furthermore, the results obtained are discussed with respect to the interaction with the homology model of the human kappa-opioid receptor, built on the recently solved crystal structure of rhodopsin. Finally, the potential antinociceptive and antiamnesic properties of compounds 6e and 6i have been investigated by means of the hot-plate and passive avoidance test in mice, respectively.
(PMID: 12930147)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Putative Target:

ChEMBL Target ID: 129
Target Type: SINGLE PROTEIN
Pref Name: Mu opioid receptor
Synonyms: hMOP;M-OR-1;MOP;MOR-1;Mu opiate receptor;Mu opioid receptor;Mu-type opioid receptor;
Gene Name: MOR1;OPRM1;
Protein Accession: P35372;
Protein GI: 2851402;
Organism: Homo sapiens
Tax ID: 9606
Target Classification: unclassified
Confidence: Homologous single protein target assigned
Relationship Type: Homologous protein target assigned
Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Binding
Assay Data Source: Scientific Literature
Result Definitions
Show more
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Ki*Ki PubChem standard valueFloatμM
3BEIBinding Efficiency Index(nM)Float
2SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6Ki activity commentKi activity commentString
7Ki standard flagKi standard flagInteger
8Ki qualifierKi qualifierString
9Ki published valueKi published valueFloatnM
10Ki standard valueKi standard valueFloatnM

* Activity Concentration.

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
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