Biochemical, functional and pharmacological characterization of novel bifunctional peptide ligands and nociceptin variants

Abstract

Since the discovery of opioid heterodimers, more and more research groups have dealt with the development of a single ligand targeting multiple opioid receptors. It is widely accepted that multitarget ligands can constitute a much more effective solution for treating certain diseases than drug cocktails. The argument is that these ligands have a better therapeutic effect and can cause fewer side effects despite binding to more than one receptors, since the receptors constitute important therapeutic targets, and the interaction between separate drugs is eliminated 126. Potential strategies include targeting receptor dimers with bifunctional or bivalent ligands. Bifunctional and bivalent drugs are not clearly distinguished from each other in the literature, and are sometimes used as synonyms. According to Dietis et al., bifunctional ligands are designed to be non-selective compounds that comprise two protein-binding drug moieties (with or without a spacer) in one chemical structure and act at two different therapeutic targets (Fig. 2) 127. Bivalent ligands, on the other hand, are intended to be selective compounds, which composed of two distinct pharmacophores joined by a linker and usually have a larger molecular weight than bifunctional ligands (Fig. 2) 128. They are usually designed to bind to their two targets, which is not always achieved in practice 127. In the present thesis, the term bifunctional shall be used to refer to our newly synthesized ligands.