This proposal is to investigate the molecular factors that affect the efficacy, potency, and receptor selectivity of conformationally flexible opioids. One approach will be to determine the biologically active conformers of compounds through MMP2 and AMBER calculations. Full energy minimization with respect to all internal coordinates will be performed to achieve quantitative results. The effect of polar and nonpolar environments on conformation will be examined by adjusting the electrostatic interactions and with Monte Carlo and molecular dynamics techniques. NMR techniques will be used to confirm some of the computational predictions. The geometries of low energy conformers will be related to pharmacological properties for structurally related opioids and across classes of opioids. Opioid classes that will be examined include 4-phenylpiperidines, methadone-like compounds such as 1-omega acetylmethadol (LAAM), as well as miscellaneous opioids with unusual properties. A second approach will be to synthesize, resolve, and assay the activities of certain conformationally homogeneous 4-phenylpiperidines. Our previous work indicates that certain of these compounds should have atypical pharmacological profiles including opioid antagonism. The objective of this work is to determine the three dimensional geometries that are associated with different pharmacological profiles. This will allow the characterization of opioids into distinct classes which may have different receptor selectivities A number of hypotheses will be tested as to the molecular features associated with certain kinds of agonism and antagonism. The long range goal of this work is to achieve a better understanding of the relationship between molecular structure of opioids and their pharmacological actions. This will be useful in the design of novel analgesics with more selective actions and fewer undesirable side effects.
