Novel Analogues of Bifunctional Ligands for Opioid and Melanocortin 4 Receptor

Kulkarni, Vinod; Lee, Yeon Sun; Salibay, Christine; Davis, Peg; Wu, Shao-Chun; Porreca, Frank; Hruby, Victor J.

doi:10.1007/978-0-387-73657-0_90

Cited by 5 publications

(3 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Various new opioid receptor ligands have been designed to target two or more opioid receptor types simultaneously, and many of these are effective in producing an analgesic response in vivo. Rational drug design and structure-activity relationship studies have evaluated the pharmacology of many of those ligands that act simultaneously on two or more different opioid receptors [242][243][244][245][246] or a combination of an opioid receptor with a non-opioid receptor [247][248][249]. For example, MDAN-21 is a mixed MOP receptor agonist/DOP receptor antagonist that is 50-fold more potent than morphine and produces less tolerance [32].…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

et al. 2021

View full text Add to dashboard Cite

Opioids are widely used as therapeutic agents against moderate to severe acute and chronic pain. Still, these classes of analgesic drugs have many potential limitations as they induce analgesic tolerance, addiction and numerous behavioural adverse effects that often result in patient non-compliance. As opium and opioids have been traditionally used as painkillers, the exact mechanisms of their adverse reactions over repeated use are multifactorial and not fully understood. Older adults suffer from cancer and non-cancer chronic pain more than younger adults, due to the physiological changes related to ageing and their reduced metabolic capabilities and thus show an increased number of adverse reactions to opioid drugs. All clinically used opioids are μ-opioid receptor agonists, and the major adverse effects are directly or potentially connected to this receptor. Multifunctional opioid ligands or peripherally restricted opioids may elicit fewer adverse effects, as shown in preclinical studies, but these results need reproducibility from further extensive clinical trials. The current review aims to overview various mechanisms involved in the adverse effects induced by opioids, to provide a better understanding of the underlying pathophysiology and, ultimately, to help develop an effective therapeutic strategy to better manage pain.

show abstract

Section: Discussion and Future Directionsmentioning

confidence: 99%

Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The choice of this pair of target receptors is justified by the mutual entanglement of the opioid and melanocortin systems in the pain transmission [ 17 , 33 , 34 ]. Earlier, a related concept was tentatively examined by Lee et al who designed bi- and trifunctional ligands based on opioid, melanocortin-4 (agonist and antagonist), and/or cholecystokinin receptor pharmacophores [ 35 , 36 ]. Those compounds, however, were not advanced to the in vivo studies.…”

Section: Discussionmentioning

confidence: 99%

Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Witkowska

Godlewska

Osiejuk

et al. 2022

IJMS

View full text Add to dashboard Cite

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.

show abstract

“…A significant contribution in this field was made by the group of Hruby, through their extensive research on the design of selective MC receptor ligands that resulted in the synthesis of SHU9119, an MC3 and MC4 receptor antagonist [91]. The finding preceded the development of the opioid (OP)-MC4 receptor bifunctional compounds [92] (however, their biological activity has not been determined) as well as trivalent opioid-melanocortin-cholecystokinin (CCK) ligands binding to the MOP, DOP, CCK1/2, and MC4 receptors [93]. SHU9119 was utilized to synthesize MOP/DOP-MC4 receptor binding hybrids with linkers of different length and rigidity.…”

Section: Mop/dop Receptor Agonist-mc4 Receptor Antagonist Hybrids Promentioning

confidence: 99%

Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges

Starnowska-Sokół

Przewłocka

2020

Molecules

View full text Add to dashboard Cite

When the first- and second-line therapeutics used to treat neuropathic pain (NP) fail to induce efficient analgesia—which is estimated to relate to more than half of the patients—opioid drugs are prescribed. Still, the pathological changes following the nerve tissue injury, i.a. pronociceptive neuropeptide systems activation, oppose the analgesic effects of opiates, enforcing the use of relatively high therapeutic doses in order to obtain satisfying pain relief. In parallel, the repeated use of opioid agonists is associated with burdensome adverse effects due to compensatory mechanisms that arise thereafter. Rational design of hybrid drugs, in which opioid ligands are combined with other pharmacophores that block the antiopioid action of pronociceptive systems, delivers the opportunity to ameliorate the NP-oriented opioid treatment via addressing neuropathological mechanisms shared both by NP and repeated exposition to opioids. Therewith, the new dually acting drugs, tailored for the specificity of NP, can gain in efficacy under nerve injury conditions and have an improved safety profile as compared to selective opioid agonists. The current review presents the latest ideas on opioid-comprising hybrid drugs designed to treat painful neuropathy, with focus on their biological action, as well as limitations and challenges related to this therapeutic approach.

show abstract

Novel Analogues of Bifunctional Ligands for Opioid and Melanocortin 4 Receptor

Cited by 5 publications

References 1 publication

Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges

Contact Info

Product

Resources

About