The research described focuses on two types of binding sites with high affinities for """"""""kappa""""""""-type opiate drugs. These sites appear to be separate entities since they differ in terms of biochemical and pharmacological characteristics and are differentially distributed in brain. One site has a high affinity for dynorphin and, therefore, corresponds to what has traditionally been termed the kappa receptor. The second site, which we refer to as T2 in this proposal, has opiate receptor characteristics but does not appear to be a kappa receptor since dynorphin and prodynorphin-related peptides have a low affinity for the site. The T2 site also has characteristics that clearly distinguish it from mu and delta opiate receptors. Thus, it is plausible that the T2 site is a major type of receptor for opiates which, heretofore, has been studied to only a limited extent. The endogenous ligand for T2 might be beta-endorphin since it has a much higher affinity for the site than other endogenous opioids. The studies in this proposal utilize recently developed drugs and procedures that distinguish between the K and T2 receptor and should contribute important information toward establishing the nature and characteristics of the sites and their biochemical and physiological functions. In addition, the latest tools of computational chemistry and molecular design be employed in the development of a truly-selective, high-affinity ligand for the T2 site. The availability of such a ligand will greatly facilitate studies of the site. We believe our extensive preliminary studies of the T2 and kappa binding sites give us a unique foundation for successfully carrying out the proposed project.
