Opioid multiple ligands

Natural and synthetic opioids are widely used in pain management. In clinical practices they are employed individually or associated with other drugs capable of modulating directly or indirectly analgesia. A combination of drugs aims to upgrade analgesia without a consequent increase in side effects. Opioid activity, including analgesia and undesirable effects, is mediated by three types of receptors called μ or MOP, δ or DOP and κ or KOP. Opioid agonists with selectivity for any of the three opioid receptor types have limitations due their adverse effects and/or weak analgesic activity. Thus, opioids are currently under experimental investigation to develop bifunctional or multifunctional drugs with more analgesic potency due to synergistic effects or, with reduced side effects than compounds acting on a single target. This current trend in medicinal chemistry research has already been reflected in a number of analgesic ligands that modulate different protein targets simultaneously. In order to pursue this objective, diverse strategies may be used; two pharmacophores from selective ligands may be connected directly or via a conjugate linker that may be cleavable or non cleavable. Moreover, it is possible to overlap the two pharmacophores to obtain slight or highly integrated pharmacophores. The current evolution of multi-target drugs in the opioid field will be described in this chapter.