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. 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.
Martínez-Mayorga
Karina
K
Torrey Pines Institute for Molecular Studies, 5775 Old Dixie Highway, Fort Pierce, FL 34946, USA. kmartinez@tpims.org
Medina-Franco
Jose L
JL
Giulianotti
Marc A
MA
Pinilla
Clemencia
C
Dooley
Colette T
CT
Appel
Jon R
JR
Houghten
Richard A
RA
D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D019295:Computational Biology; D019791:Guanidine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011957:Receptors, Opioid / Q000737:chemistry* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000737:chemistry* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
D019086:Bridged Bicyclo Compounds, Heterocyclic; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D019791:Guanidine