Grant: Operating Grant

Heptahelical receptors are the target for more than 50% of currently available therapeutic aagents. These receptors are specialized membrane proteins that allow to convey information from the extracellular to intracellular space by undergoing conformational changes upon ligand binding. The present proposal focuses on opioid receptors, their endogenous and exogenous ligands. Exogenous ligands for delta opioid receptors (DORs) are potentially powerful analgesics, but their major drawback is rapid development of tolerance. An important detereminant of tolerance is a decrease in receptor ability to generate a signal upon sustained activation, a process known as desensitization. We have recently shown that different DOR ligands stabilize different receptor conformations with distinct desensitization properties. The purpose of this study is to understand what makes some ligands produce more desensitization (and consequently more tolerance) than others. By doing so we expect to validate the general notion that it is possible to produce ligands that are capable of stimulating receptor signalling while avoiding rapid desensitization. This knowledge should be applicable not only in the production of analgesics with reduced tolerance but for the development of longer acting therapeutic agents acting at different heptahelical receptors.