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

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 11; pp. 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: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.06.2008; Elsevier Science
• 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; Multi-fusion similarity maps; Mixture-based combinatorial libraries; Structure–activity relationships; Opioid receptor ligands; Molecular similarity; Similarity; Ligand; Combinatorial chemistry; κ Opioid receptor; Guanidines; Structure-activity relationships; Three dimensional model; Structure activity relation; Chemical compound library; Bicyclic compound; Conformation
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.04.061

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.