The long-term objectives of this project are the development of selective nonpeptide ligands as tools to investigate the opioid receptor family and closely related homologous receptors. These ligands will be used in pharmacological studies to investigate the roles of receptor types and subtypes, and as tools that may lead to the discovery of new receptors in the opioid receptor family. Also, the ligands will be employed to probe the molecular architecture of different opioid receptor recognition sites through a combination of molecular modeling and binding studies to cloned wild-type and mutant receptors. Potential clinical applications of ligands developed in this laboratory will be pursued on a collaborative basis in the areas of substance abuse, analgesia and HIV-1.
The specific aims of this application include the following projects: a) Synthesis and biological evaluation of morphinans that contain aromatic groups that are restricted to a variety of specific conformations in an effort to develop delta subtype-selective antagonists; b) Synthesis of conformationally constrained amidines derived mainly from naltrexone, in an effort to obtain subtype-selective kappa antagonists. Members of these series also will be tested on cloned wild-type and mutant kappa receptors in order to obtain information on the antagonist recognition site; c) The synthesis and evaluation of kappa agonists that have greatly restricted capacity to enter the CNS when administered peripherally. Members of this series are of interest as pharmacologic tools to investigate peripheral kappa receptors without involvement of central kappa receptors; d) The design and synthesis of kappa receptor affinity labels that are structurally related to known kappa antagonists. These ligands have potential uses as pharmacologic tools and as probes to identify residues at the antagonist recognition site; e) The development of selective antagonists for the lymphocyte-derived opioid receptor that appears to be a delta subtype. This will involve the screening of selected compounds from the P.I.'s library of opioid ligands in an effort to obtain lead compounds. Modeling studies will be conducted based on differences between the neuronal and lymphocyte-derived receptors in an effort to obtain information on the recognition sites; and f) The development of ORLl-selective nonpeptide ligands from leads obtained from the P.I.'s library of opioid ligands.
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