Background
Metabolomics is a well-established rapidly developing research field involving quantitative and qualitative metabolite assessment within biological systems. Recent improvements in metabolomics technologies reveal the unequivocal value of metabolomics tools in natural products discovery, gene-function analysis, systems biology and diagnostic platforms.
Scope of review
We review of some of the prominent metabolomics methodologies employed in data acquisition and analysis of natural products and disease-related biomarkers.
Major conclusions
This review demonstrates that metabolomics represents a highly adaptable technology with diverse applications ranging from environmental toxicology to disease diagnosis. Metabolomic analysis is shown to provide a unique snapshot of the functional genetic status of an organism by examining its biochemical profile, with relevance toward resolving phylogenetic associations involving horizontal gene transfer and distinguishing subgroups of genera possessing high genetic homology, as well as an increasing role in both elucidating biosynthetic transformations of natural products and detecting preclinical biomarkers of numerous disease states.
General significance
This review expands the interest in multiplatform combinatorial metabolomic analysis. The applications reviewed range from phylogenetic assignment, biosynthetic transformations of natural products, and the detection of preclinical biomarkers.
Background:
Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects.
Aims:
In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities.
Methods:
Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins.
Results/outcomes:
Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin.
Conclusions/interpretation:
By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.
Analgesia
is commonly mediated through the mu or kappa opioid receptor agonism.
Unfortunately, selective mu or kappa receptor agonists often cause harmful side
effects. Recently, ligands exhibiting dual agonism to the opioid receptors,
such as to mu and kappa, or to mu and delta, have been suggested to temper
undesirable adverse effects while retaining analgesic activity. Herein we report
an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies
showed that some of these compounds have dual agonism on kappa and mu opioid
receptors, while some have triple agonism on kappa, mu, and delta. <i>In
vivo </i>studies on the lead dual kappa and mu opioid receptor agonist,
compound <b>10</b>, showed that it<b> </b>produced
analgesic activity while avoiding anxiogenic effects in murine models, thus
providing further strong evidence for the therapeutic advantages of dual opioid
receptor agonists over selective opioid receptor agonists.
Current common analgesics are mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. However, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that many of these compounds have dual agonism on kappa and mu opioid receptors. In vivo studies on the lead dual kappa and mu opioid receptor agonist demonstrated supraspinal thermal analgesic activity while avoiding anxiogenic effects in male mice, thus providing further strong evidence in support of the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.
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