General approach leading to the development of imidazoquinoline and imidazopyrimidine benzodiazepine receptor ligands

Abstract The observation that the imidazoquinoxaline ethyl ester RU32180 possessed an affinity of 175 nM for benzodiazepine (BDZ) receptors led to the discovery of several series of potent receptor ligands such as esters ofimidazoquinolines and imidazobenzothiazoles. The lack of oral activity shown by these esters was rectified in the benzoyl imidazoquinolne RU31719, which possessed nearly all the properties of a classical BDZ agonist but with reduced muscle relaxant activity. Structure‐activity studies led to the benzoyl imidazoquinazoline RU32514 and from there to the imidazopyrimidine RU32698, which has robust anxiolytic activity, but induces little sedation and no muscle relaxation in a range of animal models. Further studies yielded the oxadiazolyl imidazopyrimidines such as RU33203, a potent partial agonist, and the thiazolyl imidazopyrimidine RU33356, the first member of the series to possess antagonist/inverse agonist properties.