Photoaffinity labeling and macrocyclic spiro bicylic analogs of the dopamine receptor modulator L-prolyl-L-leucyl-glycinamide

L-Prolyl-L-leucyl-glycinamide (PLG) possesses the unique ability to modulate dopamine receptors in the central nervous system. The precise binding site, however, is not known. Photoaffinity labeling ligands for the putative PLG binding site have been synthesized in order to identify the macromolecule that possesses the PLG binding site. Six different photoaffinity labeling ligands have been synthesized. These molecules posses either the photolabile 4-azidobenzoyl or 4-azido-2-hydroxybenzoyl moiety. These two different moieties were placed at opposite ends of the parent peptidomimetic as a way of mapping the PLG binding site. All of the compounds that were tested were as effective as PLG in enhancing dopamine agonist, [3H]NPA, binding. Tests conducted also indicate that these compounds are binding at the same site as PLG or the parent peptidomimetic. The efficiency at which these compounds enhance dopamine agonist binding indicates that they can be used as probes of the PLG binding site.; The bioactive conformation of PLG is believed to be that of a type II beta-turn. Various peptidomimetics have been synthesized that constrain one, two, or three of the four torsion angles to values seen in a type II beta-turn. One of the most potent compounds consists of a 5.6.5 spirobicycle ring system. The lone variable that remains is constraining all four torsion angles to a value seen in a type II beta-turn. Four different macrocycles have been synthesized that are composed of the spirobicycle and formed using either ring closing metathesis or cyclization.