Pain is associated with many health problems and a reduced quality of life and has been a common reason for seeking medical attention. Several therapeutics are available on the market, although side ...effects, physical dependence, and abuse limit their use. As the process of pain transmission and modulation is regulated by different peripheral and central mechanisms and neurotransmitters, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery due to their chemical structural variety and different analgesic mechanisms. Numerous studies suggested that some chemicals from medicinal plants could be alternative options for pain relief and management. Previously, we conducted a literature search aimed at identifying natural products interacting either directly or indirectly with opioid receptors. In this review, instead, we have made an excursus including active ingredients derived from plants whose mechanism of action appears from the literature to be other than the modulation of the opioid system. These substances could, either by themselves or through synthetic and/or semi-synthetic derivatives, be investigated in order to improve their pharmacokinetic characteristics and could represent a valid alternative to the opioid approach to pain therapy. They could also be the basis for the study of new mechanisms of action in the approach to this complex and disabling pathology.
Pain continues to be an enormous global health challenge, with millions of new untreated or inadequately treated patients reported annually. With respect to current clinical applications, opioids ...remain the mainstay for the treatment of pain, although they are often associated with serious side effects. To optimize their tolerability profiles, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery, and they hold potential for pain management. Traditional medicine has had a long history in clinical practice due to the fact that nature provides a rich source of active principles. For instance, opium had been used for pain management until the 19th century when its individual components, such as morphine, were purified and identified. In this review article, we conducted a literature survey aimed at identifying natural products interacting either directly with opioid receptors or indirectly through other mechanisms controlling opioid receptor signaling, whose structures could be interesting from a drug design perspective.
Lipid nanocarriers show occlusive properties that may be related to their ability to improve skin hydration. The aim of this work was to evaluate the relationship between in vitro occlusion factor ...and in vivo skin hydration for three types of lipid nanocarriers: nanoemulsions (NEs), solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). These lipid nanocarriers were loaded with
-resveratrol (RSV) and incorporated in gel vehicles. In vitro occlusion factor was in the order SLNs > NLCs > NEs. Gels containing unloaded or RSV loaded lipid nanocarriers were applied on the back of a hand of 12 healthy volunteers twice a day for one week, recording skin hydration changes using the instrument Soft Plus. An increase of skin hydration was observed for all lipid nanocarriers (SLNs > NLCs > NEs). RSV loading into these nanocarriers did not affect in vitro and in vivo lipid nanocarriers effects. A linear relationship (
² = 0.969) was observed between occlusion factor and in vivo increase of skin hydration. Therefore, the results of this study showed the feasibility of using the occlusion factor to predict in vivo skin hydration resulting from topical application of different lipid nanocarriers loading an active ingredient with no inherent hydrating activity.
Although persistent pain is estimated to affect about 20% of the adult population, current treatments have poor results. Polypharmacology, which is the administration of more than one drug targeting ...on two or more different sites of action, represents a prominent therapeutic approach for the clinical management of persistent pain. Thus, in the drug discovery process the “one-molecule-multiple targets” strategy nowadays is highly recognized. Indeed, multitarget ligands displaying a better antinociceptive activity with fewer side effects, combined with favorable pharmacokinetic and pharmacodynamic characteristics, have already been shown. Multitarget ligands possessing non-opioid/opioid and opioid/opioid mechanisms of action are considered as potential drug candidates for the management of various pain conditions. In particular, dual-target MOPr (mu opioid peptide receptor)/DOPr (delta opioid peptide receptor) ligands exhibit an improved antinociceptive profile associated with a reduced tolerance-inducing capability. The benzomorphan-based compounds LP1 and LP2 belong to this class of dual-target MOPr/DOPr ligands. In the present manuscript, the structure–activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as suitable drug candidates for persistent pain relief is described.
Opioid analgesics have been used for thousands of years in the treatment of pain and related disorders, and have become among the most widely prescribed medications. Among opioid analgesics, mu ...opioid receptor (MOR) agonists are the most commonly used and are indicated for acute and chronic pain management. However, their use results in a plethora of well-described side-effects. From selective delta opioid receptor (DOR) and kappa opioid receptor (KOR) agonists to multitarget MOR/DOR and MOR/KOR ligands, medicinal chemistry provided different approaches aimed at the development of opioid analgesics with an improved pharmacological and tolerability fingerprint. The emergent medicinal chemistry strategy to develop ameliorated opioid analgesics is based upon the concept that functional selectivity for G-protein signalling is necessary for the therapeutic effect, whether β-arrestin recruitment is mainly responsible for the manifestation of side effects, including the development of tolerance after repeated administrations. This review summarises most relevant biased MOR, DOR, KOR and multitarget MOR/DOR ligands synthesised in the last decade and their pharmacological profile in “in vitro” and “in vivo” studies. Such biased ligands could have a significant impact on modern drug discovery and represent a new strategy for the development of better-tolerated drug candidates.
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•Opioid ligands with functional selectivity possess an improved pharmacological fingerprint.•Opioid biased ligands activate preferentially G-protein signalling over β-arrestin.•Biased MOR, DOR, KOR and MOR/DOR agonist structure activity relationships were described.•Molecular modelling and computational studies were reported.
Background
Neuropathic pain is caused by primary lesion or dysfunction of either peripheral or central nervous system. Due to its complex pathogenesis, often related to a number of comorbidities, ...such as cancer, neurodegenerative and neurovascular diseases, neuropathic pain still represents an unmet clinical need, lacking long-term effective treatment and complex case-by-case approach.
Aim and methods
We analyzed the recent literature on the role of selective voltage-sensitive sodium, calcium and potassium permeable channels and non-selective gap junctions (GJs) and hemichannels (HCs) in establishing and maintaining chronic neuropathic conditions. We finally focussed our review on the role of extracellular microenvironment modifications induced by resident glial cells and on the recent advances in cell-to-cell and cell-to-extracellular environment communication in chronic neuropathies.
Conclusion
In this review, we provide an update on the current knowledge of neuropathy chronicization processes with a focus on both neuronal and glial ion channels, as well as on channel-mediated intercellular communication.
Sigma receptors are a fascinating receptor protein class whose ligands are actually under clinical evaluation for the modulation of opioid analgesia and their use as positron emission tomography ...radiotracers. In particular, peculiar biological and therapeutic functions are associated with the sigma-2 (σ₂) receptor. The
₂ receptor ligands determine tumor cell death through apoptotic and non-apoptotic pathways, and the overexpression of
₂ receptors in several tumor cell lines has been well documented, with significantly higher levels in proliferating tumor cells compared to quiescent ones. This acknowledged feature has found practical application in the development of cancer cell tracers and for ligand-targeting therapy. In this context, the development of new ligands that target the
₂ receptors is beneficial for those diseases in which this protein is involved. In this paper, we conducted a search of new potential
₂ receptor ligands among a database of 1517 "small" marine natural products constructed by the union of the Seaweed Metabolite and the Chemical Entities of Biological Interest (ChEBI) Databases. The structures were passed through two filters that were constituted by our developed two-dimensional (2D) and three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) statistical models, and successively docked upon a
₂ receptor homology model that we built according to the FASTA sequence of the
₂/TMEM97 (SGMR2_HUMAN) receptor.
Although rosemary essential oil (EO) shows many biological activities, its topical benefits have not been clearly demonstrated. In this work, we assessed the effects on skin hydration and elasticity ...of rosemary EO after topical application via gel vehicles in human volunteers. To improve its topical efficacy, rosemary EO was loaded into lipid nanoparticles (NLCs) consisting of cetyl palmitate as a solid lipid, and non-ionic surfactants. Such NLCs were prepared using different ratios of EO/solid lipid and those containing EO 3%
/
and cetyl pamitate 7%
/
were selected for in vivo studies, showing the best technological properties (small particle size, low polydispersity index and good stability). Gels containing free EO or EO-loaded NLCs were applied on the hand skin surface of ten healthy volunteers twice a day for one week. Skin hydration and elasticity changes were recorded using the instrument Soft Plus. Gels containing EO-loaded NLCs showed a significant increase in skin hydration in comparison with gels containing free EO. Skin elasticity increased, as well, although to a lesser extent. The results of this study point out the usefulness of rosemary EO-loaded NLCs for the treatment of cutaneous alterations involving loss of skin hydration and elasticity.
Chronic neuropathic pain emerges from either central or peripheral lesions inducing spontaneous or amplified responses to non-noxious stimuli. Despite different pharmacological approaches to treat ...such a chronic disease, neuropathic pain still represents an unmet clinical need, due to long-term therapeutic regimens and severe side effects that limit application of currently available drugs. A critical phenomenon involved in central sensitization is the exchange of signalling molecules and cytokines, between glia and neurons, driving the chronicization process. Herein, using a chronic constriction injury (CCI) model of neuropathic pain, we evaluated the efficacy of the mu (M-) and delta (D-) opioid receptor (-OR) targeting agent LP2 in modulating connexin-based heterocellular coupling and cytokine levels. We found that long-term efficacy of LP2 is consequent to MOR-DOR targeting resulting in the reduction of CCI-induced astrocyte-to-microglia heterocellular coupling mediated by connexin 43. We also found that single targeting of DOR reduces TNF and IL-6 levels in the chronic phase of the disease, but the peripheral and central discharge as the primary source of excitotoxic stimulation in the spinal cord requires a simultaneous MOR-DOR targeting to reduce CCI-induced neuropathic pain.
In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate compounds with improved analgesia. ...To do that, the phenyl ring in the
-substituent of our lead compound LP1 was replaced by an electron-rich or electron-deficient ring and linked through a propanamide or butyramide spacer at the basic nitrogen of the (-)-
-
-normetazocine skeleton. In radioligand binding assays, compounds
and
were found to display nanomolar binding affinity for the μ opioid receptor (MOR) (K
= 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound
showed an antagonist effect against DAMGO (D-Ala
, N-MePhe
, Gly-ol-enkephalin), a highly selective MOR prototype agonist, whereas compound
produced naloxone reversible effect at MOR. Moreover, compound
, as potent as LP1 and DAMGO at MOR, was able to reduce thermal and inflammatory pain assessed by the mouse tail-flick test and rat paw pressure thresholds (PPTs) measured by a Randall-Selitto test.
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