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

Karina Martínez-Mayorga; Jose L. Medina-Franco; Marc A. Giulianotti; Clemencia Pinilla; Colette T. Dooley; Jon R. Appel; Richard A. Houghten

doi:10.1016/j.bmc.2008.04.061

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

Karina Martínez-Mayorga, Jose L. Medina-Franco, Marc A. Giulianotti, Clemencia Pinilla, Colette T. Dooley, Jon R. Appel, Richard A. Houghten

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	5932-5938
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	16
Issue number	11
DOIs	https://doi.org/10.1016/j.bmc.2008.04.061
State	Published - Jun 1 2008
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the State of Florida, Executive Officer of the Governor’s Office of Tourism, Trade and Economic Development. The authors are also grateful to the National Institute on Drug Abuse (DA019620) and to the Multiple Sclerosis National Research Institute for partial funding. The authors acknowledge OpenEye Scientific Software, INC. for providing ROCS, OMEGA and VIDA programs.

Keywords

Mixture-based combinatorial libraries
Molecular similarity
Multi-fusion similarity maps
Opioid receptor ligands
Structure-activity relationships

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10.1016/j.bmc.2008.04.061

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title = "Conformation-opioid activity relationships of bicyclic guanidines from 3D similarity analysis",

abstract = "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.",

keywords = "Mixture-based combinatorial libraries, Molecular similarity, Multi-fusion similarity maps, Opioid receptor ligands, Structure-activity relationships",

author = "Karina Mart{\'i}nez-Mayorga and Medina-Franco, \{Jose L.\} and Giulianotti, \{Marc A.\} and Clemencia Pinilla and Dooley, \{Colette T.\} and Appel, \{Jon R.\} and Houghten, \{Richard A.\}",

note = "Funding Information: This work was supported by the State of Florida, Executive Officer of the Governor{\textquoteright}s Office of Tourism, Trade and Economic Development. The authors are also grateful to the National Institute on Drug Abuse (DA019620) and to the Multiple Sclerosis National Research Institute for partial funding. The authors acknowledge OpenEye Scientific Software, INC. for providing ROCS, OMEGA and VIDA programs.",

year = "2008",

month = jun,

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doi = "10.1016/j.bmc.2008.04.061",

language = "English (US)",

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T1 - Conformation-opioid activity relationships of bicyclic guanidines from 3D similarity analysis

AU - Martínez-Mayorga, Karina

AU - Medina-Franco, Jose L.

AU - Giulianotti, Marc A.

AU - Pinilla, Clemencia

AU - Dooley, Colette T.

AU - Appel, Jon R.

AU - Houghten, Richard A.

N1 - Funding Information: This work was supported by the State of Florida, Executive Officer of the Governor’s Office of Tourism, Trade and Economic Development. The authors are also grateful to the National Institute on Drug Abuse (DA019620) and to the Multiple Sclerosis National Research Institute for partial funding. The authors acknowledge OpenEye Scientific Software, INC. for providing ROCS, OMEGA and VIDA programs.

PY - 2008/6/1

Y1 - 2008/6/1

N2 - 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.

AB - 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.

KW - Mixture-based combinatorial libraries

KW - Molecular similarity

KW - Multi-fusion similarity maps

KW - Opioid receptor ligands

KW - Structure-activity relationships

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AN - SCOPUS:44449163419

SN - 0968-0896

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JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 11

ER -

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

Abstract

Bibliographical note

Keywords

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