Abstract
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 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.
Highlights
Due to their role in pain perception and modulation, opioid receptors (μ, δ, and κ, or MOR, DOR, and KOR, respectively) are very important targets in medicinal chemistry
The peptides were synthesized by the solid-phase procedure using Fmoc/tBu chemistry with the hyper-acid labile Mtt/O-2 PhiPr groups for selective protection of amine/carboxyl side-chain groups engaged in the formation of the cyclic fragment
All compounds were purified by semipreparative RP HPLC, and their identity was confirmed by high-resolution mass spectrometry (ESI-HRMS)
Summary
Due to their role in pain perception and modulation, opioid receptors (μ, δ, and κ, or MOR, DOR, and KOR, respectively) are very important targets in medicinal chemistry. The plant alkaloid morphine and its derivatives, which elicit their analgesic effect mostly through the activation of MOR [1], are often the only choice for the management of severe pain [2]. The long-term use of these drugs in chronic pain states causes the development of tolerance, which in turn necessitates dose escalation [3]. The dissociation of analgesia from the adverse side effects elicited by MOR agonists is the main goal in the search for better and safer analgesics. Compounds with a MOR agonist/DOR antagonist profile showed fewer side effects and enhanced efficacy [8]
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