Title:Hybrid Opioid/Non-Opioid Ligands in Pain Research
VOLUME: 19 ISSUE: 42
Author(s):Patrycja Kleczkowska, Andrzej W. Lipkowski, Dirk Tourwe and Steven Ballet
Affiliation:Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
Keywords:Opioid receptors, bi- or multifunctional compounds, opioid analgesics, designed multiple ligands.
Abstract:To address the different types of pain (e.g. acute, chronic, neuropathic) different classes of medications, mainly non-steroidal
anti-inflammatory drugs and narcotics (opioids), are used. More specifically, the alleviation or treatment of moderate to severe pain states
commonly invokes the use of opioids. Unfortunately, their chronic administration induces various undesirable side effects, such as for
example physical dependence and tolerance. One strategy to overcome these major side effects and to prolong the antinociceptive efficiency
of the applied drugs involves the creation of multifunctional compounds which contain hybridized structures. Combination of
opioid agonist and antagonist pharmacophores in a single chemical entity has been considered and extensively investigated, but opioids
have also been combined with other bioactive neurotransmitters and peptide hormones that are involved in pain perception (e.g. substance
P, neurotensin, cholecystokinin, cannabinoids, melanocortin ligands, etc.). Such novel chimeras (also called designed multiple
ligands or twin/triplet drugs), may interact independently with their respective receptors and potentially result in more effective antinociceptive
properties. The designed multiple ligands presented in this work include opioid-non-opioid peptide dimer analogs, mixed peptidic-
non-peptidic bifunctional ligands and dual non-peptidic dimers. The main focus herein is placed on the design and biological
evaluation of these multiple opioid compounds, rather than the synthetic approach and preparation.
