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BioAssay: AID 647793

Antinociceptive activity in sc dosed mouse

A simple three-step synthesis of 5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-4-ol (3a) was achieved using an osmium tetroxide mediated oxidation of the known intermediate 6. A pyrrolidine-ring variant of 3a (3-(7-(hydroxymethyl)-6-methyl-6-azabicyclo[3.2.1]octan-1-yl)phenol (5)) was isolated when other routes were used. The epimeric hydroxy analogue 4a was synthesized by simple more ..
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 Tested Compounds
 Tested Compounds
All(4)
 
 
Unspecified(4)
 
 
 Tested Substances
 Tested Substances
All(4)
 
 
Unspecified(4)
 
 
 Related BioAssays
 Related BioAssays
AID: 647793
Data Source: ChEMBL (805241)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2012-09-09
Modify Date: 2014-05-25

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Tested Compounds:
Description:
Title: Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective mu-antagonist activity.

Abstract: A simple three-step synthesis of 5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-4-ol (3a) was achieved using an osmium tetroxide mediated oxidation of the known intermediate 6. A pyrrolidine-ring variant of 3a (3-(7-(hydroxymethyl)-6-methyl-6-azabicyclo[3.2.1]octan-1-yl)phenol (5)) was isolated when other routes were used. The epimeric hydroxy analogue 4a was synthesized by simple inversion of the stereochemistry at C-4. Both N-methyl (3a and 4a) and N-phenethyl (3b and 4b) derivatives were synthesized. The compounds were examined for their opioid receptor affinity and the N-phenethyl analogue 3b was found to have relatively weak affinity for the mu-opioid receptor (K(i)#=#74#nM). However, the N-phenethyl analogue of the C-4 epimer, 4b, had about 15 fold higher affinity than 3b and was selective for the mu-opioid receptor (K(i)#=#4.6#nM). Compound 4b was a moderately potent mu-opioid antagonist (K(e)#=#12#nM), as determined by [(35)S]GTP-gamma-S assays. Compounds 3b and 4b were energy minimized at the level of B3LYP/6-31G*, and then overlaid onto the 5-phenylmorphan, the (1R,5R,9S)-(-)-enantiomer of 2b (Fig.#1) with the alpha or beta-OH group at the C-9 position. The spatial orientation of the hydroxyl moiety in 3b, 4b, 2a, and 2b is proposed to be the structural requirement for high mu-opioid receptor binding affinity and their agonist or antagonist activity. The modest change in spatial position of the hydroxyl moiety, and not the N-substituent, induced the change from potent agonist to an antagonist of moderate potency.
(PMID: 22341895)
Comment
Putative Target:

ChEMBL Target ID: 50594
Target Type: ORGANISM
Pref Name: Mus musculus
Organism: Mus musculus
Tax ID: 10090
Confidence: Target assigned is non-molecular
Relationship Type: Non-molecular target assigned
Categorized Comment - additional comments and annotations
From ChEMBL:
Assay Type: Functional
Assay Data Source: Scientific Literature
BAO: Assay Format: organism-based format
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1ED50 activity commentED50 activity commentString
2ED50 standard flagED50 standard flagInteger
3ED50 qualifierED50 qualifierString
4ED50 published valueED50 published valueFloatmg kg-1
5ED50 standard valueED50 standard valueFloatmg.kg-1

Data Table (Concise)
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