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/6-31 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. 1. Introduction 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. Concerning the recognition by a drug of one or more receptors, this is a phenomenon that still needs to be fully understood to design new agonists or antagonists for a given receptor type. The central problem of the drug-receptor interaction is the following: how can a certain molecule be recognized by two or more receptors and display different affinities for them? Among the molecules having this interesting property we may cite dopaminergic, serotoninergic, and opioid compounds. In the following we shall focus on the latter. Regarding opioids there is abundant evidence for the existence of four major classes of receptors in the central nervous system (CNS), designated as , , , and nociceptin, as well as subtypes within the first three classes (we employed capital letters to avoid confusions because similar small Greek letters are used to design reactivity indices used below). Each receptor type has a distinct selectivity profile and a unique distribution within
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