Molecules, Vol. 24, Pages 4460: Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

Molecules, Vol. 24, Pages 4460: Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors Molecules doi: 10.3390/molecules24244460 Authors: Karol Wtorek Anna Adamska-Bartłomiejczyk Justyna Piekielna-Ciesielska Federica Ferrari Chiara Ruzza Alicja Kluczyk Joanna Piasecka-Zelga Girolamo Calo’ Anna Janecka Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure–activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research