Abstract
We report the results of a search for model-based relationships between mu, delta, and kappa opioid receptor binding affinity and molecular structure for a group of molecules having in common a morphine structural core. The wave functions and local reactivity indices were obtained at the ZINDO/1 and B3LYP/6-31G∗∗ levels of theory for comparison. New developments in the expression for the drug-receptor interaction energy expression allowed several local atomic reactivity indices to be included, such as local electronic chemical potential, local hardness, and local electrophilicity. These indices, together with a new proposal for the ordering of the independent variables, were incorporated in the statistical study. We found and discussed several statistically significant relationships for mu, delta, and kappa opioid receptor binding affinity at both levels of theory. Some of the new local reactivity indices incorporated in the theory appear in several equations for the first time in the history of model-based equations. Interaction pharmacophores were generated for mu, delta, and kappa receptors. We discuss possible differences regulating binding and selectivity in opioid receptor subtypes. This study, contrarily to the statistically backed ones, is able to provide a microscopic insight of the mechanisms involved in the binding process.
Highlights
Molecular recognition processes control a huge number of aspects of life on Earth
The ability of molecules to recognize a certain pattern of atom distribution and not another is central to catalysis, drug effects, chemical reactivity, and so forth
In our Laboratory, and using a modelbased method, we have addressed this question through the analysis of the different modes of binding of molecules to μ, δ, and κ opiate receptors in order to generate a binding pharmacophore [29,30,31]
Summary
Molecular recognition processes control a huge number of aspects of life on Earth. The ability of molecules to recognize a certain pattern of atom distribution and not another is central to catalysis, drug effects, chemical reactivity, and so forth. This paper uses quantum chemical methods in an attempt to advance the knowledge of the relationship between electronic structure and the binding to μ, δ, and κ receptors in a series of high affinity opioid receptor ligands, whereby the phenolic OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone, and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives to the receptor It was during the second half of the 1950 decade when the first applications of Molecular Orbital (MO) theory to the study of questions of pharmacological interest began to appear in the scientific literature [32,33,34,35]. This must be done for all atoms entering in the multiple regression analysis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
