Biphalin: The Foundation of Bivalent Ligands

Seldom in medicinal chemistry does one ligand present the ability to study two separate phenomena in a pharmacological process. The discovery of biphalin with other homodimeric ligands has given scientists a tool that not only explores how to increase the efficacy of the ligand, but also explore the possible interactions of hetero and homo dimerization of the receptors themselves. As a straight ligand, biphalin has allowed scientists to increase efficacy by direct modification of the residues to affect the message-address interactions with receptors. This led to the exploration of ligand linkers to increase efficacy and it was this modification of the linkers led to discoveries that suggested dimerization of receptor system occurs as a secondary modulation of signal transduction. Even more recently, exploration of the advances in linkers through the discovery of bitopicity seems to modulate the actual receptors to increase the binding and signal transdcution of the ligand. This is accomplished by possible slight conformational changes in the receptors before binding of the ligand located at the end of the linker. These advances were made by the work of the late Prof. Andrzej W. Lipkowski. This review gives the foundation of biphalin and in turn celebrates the contributions of Prof. Lipkowski made in this area. Keywords: Biphalin, Bivalent ligands, Pain, Opioid receptors, Receptor dimerization, Side effects.