Pain remains a key therapeutic area with intensive efforts directed toward finding effective and safer analgesics in light of the ongoing opioid crisis. Amongst the neurotransmitter systems involved in pain perception and modulation, the mu-opioid receptor (MOR), a G protein-coupled receptor, represents one of the most important targets for achieving effective pain relief. Most clinically used opioid analgesics are agonists to the MOR, but they can also cause severe side effects. Medicinal plants represent important sources of new drug candidates, with morphine and its semisynthetic analogues as well-known examples as analgesic drugs. In this study, combining in silico (pharmacophorebased virtual screening and docking) and pharmacological (in vitro binding and functional assays, and behavioral tests) approaches, we report on the discovery of two naturally occurring plant alkaloids, corydine and corydaline, as new MOR agonists that produce antinociceptive effects in mice after subcutaneous administration via a MOR-dependent mechanism. Furthermore, corydine and corydaline were identified as G protein-biased agonists to the MOR without inducing β-arrestin2 recruitment upon receptor activation. Thus, these new scaffolds represent valuable starting points for future chemical optimization towards the development of novel opioid analgesics, which may exhibit improved therapeutic profiles. Naturally occurring opioid alkaloids, such as morphine (Fig. 1), have been used for centuries for severe and chronic pain relief 1. Over several decades, new opioids with diverse scaffolds were synthesized, pharmacologically evaluated and clinically used as the most effective class of analgesic drugs 2-5. However, all currently available opioid analgesics share a similar spectrum of undesirable side effects, including respiratory depression, constipation, sedation, nausea and analgesic tolerance 5,6. Additionally, the potential for addiction and abuse of opioids has seriously hindered their clinical application, with a huge rise in opioid misuse and overdose deaths resulting in an ongoing and rapidly emerging opioid epidemic worldwide 7,8. Currently, intensive research focuses on finding new, innovative medications and technologies to treat opioid addiction, together with the discovery of safe, effective, non-addictive drugs to manage chronic pain 9-12. Opioids produce their pharmacological effects through the activation of opioid receptors, which include three main types, mu (MOR), delta (DOR) and kappa (KOR) 13,14 , of which the MOR type is the primary target of most clinically used opioid analgesics 3,5. Opioid receptors share high homology and belong to the superfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs). Because of its therapeutic relevance, the MOR is among the few GPCRs determined in different activation states, with the first X-ray crystal structure of the receptor protein bound to β-funaltrexamine (Fig. 1), an irreversible antagonist (PDB entry 4DKL) 15 , and the 3D-structure in the active confo...
Oplopanax horridus and Panax ginseng are members of the plant family Araliaceae, which is rich in structurally diverse polyacetylenes. In this work, we isolated and determined structures of 23 aliphatic C17 and C18 polyacetylenes, of which five are new compounds. Polyacetylenes have a suitable scaffold for binding to PPARγ, a ligand-activated transcription factor involved in metabolic regulation. Using a reporter gene assay, their potential was investigated to activate PPARγ. The majority of the polyacetylenes showed at least some PPARγ activity, among which oplopantriol B 18-acetate (1) and oplopantriol B (2) were the most potent partial PPARγ activators. By employing in silico molecular docking and comparing the activities of structural analogues, features are described that are involved in PPARγ activation, as well as in cytotoxicity. It was found that the type of C-1 to C-2 bond, the polarity of the terminal alkyl chain, and the backbone flexibility can impact bioactivity of polyacetylenes, while diol structures with a C-1 to C-2 double bond showed enhanced cytotoxicity. Since PPARγ activators have antidiabetic and anti-inflammatory properties, the present results may help explain some of the beneficial effects observed in the traditional use of O. horridus extracts. Additionally, they might guide the polyacetylene-based design of future PPARγ partial agonists.
The total syntheses of all stereoisomers of notoincisol A, a recently isolated natural product with potential anti-inflammatory activity, are reported. The asymmetric synthesis was conducted employing a lipase-mediated kinetic resolution, which enables easy access to all required chiral building blocks with the aim of establishing the absolute configuration of the naturally occurring isomer. This was achieved by comparison of optical properties of the isolated compound with the synthetic derivatives obtained. Moreover, an assessment of the biological activity on PPARγ (peroxisome proliferator-activated receptor gamma) as a prominent receptor related to inflammation is reported. Only the natural isomer was found to activate the PPARγ receptor, and this phenomenon could be explained based on molecular docking studies. In addition, the pharmacological profiles of the isomers were determined using the GABAA (gamma-aminobutyric acid A) ion channel receptor as a representative target for allosteric modulation related to diverse CNS activities. These compounds were found to be weak allosteric modulators of the α1β3 and α1β2γ2 receptor subtypes.
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