Conformation-opioid activity relationships of bicyclic guanidines from 3D similarity analysis

Conformation of bicyclic guanidines with kappa-opioid receptor activity derived in our laboratory from a positional scanning synthetic combinatorial library is presented in this work. We propose a common bioactive conformation and putative pharmacophoric features by means of 3D similarity methods. O...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-06, Vol.16 (11), p.5932-5938
Main Authors: Martínez-Mayorga, Karina, Medina-Franco, Jose L., Giulianotti, Marc A., Pinilla, Clemencia, Dooley, Colette T., Appel, Jon R., Houghten, Richard A.
Format: Article
Language:English
Subjects:
Binding Sites
Biological and medical sciences
Bridged Bicyclo Compounds, Heterocyclic - chemistry
Bridged Bicyclo Compounds, Heterocyclic - metabolism
Combinatorial Chemistry Techniques
Computational Biology
Guanidine - analogs & derivatives
Guanidine - chemistry
Guanidine - metabolism
Medical sciences
Mixture-based combinatorial libraries
Molecular similarity
Multi-fusion similarity maps
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Nucleic Acid Conformation
Opioid receptor ligands
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Receptors, Opioid - chemistry
Receptors, Opioid - metabolism
Receptors, Opioid, delta - chemistry
Receptors, Opioid, delta - metabolism
Receptors, Opioid, mu - chemistry
Receptors, Opioid, mu - metabolism
Structure–activity relationships
Thermodynamics
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Summary:Conformation of bicyclic guanidines with kappa-opioid receptor activity derived in our laboratory from a positional scanning synthetic combinatorial library is presented in this work. We propose a common bioactive conformation and putative pharmacophoric features by means of 3D similarity methods. Our ‘Y’ shape molecular binding model explains structure–activity relationships and suggests that the guanidine functionality and a 4-methoxybenzyl group may be involved in key interactions with the receptor. Comparison of our model with known opiates suggest a similar binding mode showing that the bicyclic guanidines presented in this work are suitable scaffolds for further development of new opioid receptors ligands.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.04.061