Supplementary data for the article: Jevtić, I. I.; Savić Vujović, K.; Srebro, D.; Vučković, S.; Ivanović, M. D.; Kostić-Rajačić, S. V. Synthesis and Pharmacological Evaluation of Novel Cis and Trans 3-Substituted Anilidopiperidines. Pharmacol. Rep 2020, 72 (4), 1069–1075. https://doi.org/10.1007/s43440-020-00121-2

Supplementary material for: [ https://doi.org/10.1007/s43440-020-00121-2]Related to published version: [https://cherry.chem.bg.ac.rs/handle/123456789/4211

TRPV1: A Promising drug target for the treatment of various conditions

Nobelova nagrada za fiziologiju i medicinu za 2021. dodeljena je naučnicima koji su identifikovali receptore za temperaturu i dodir. Da bi sproveli ovo ispitivanje, istraživači su koristili kapsaicin, jedinjenje koje čili paprici daje toplotu, kako bi otkrili receptore koji omogućavaju ljudima da osete “gorući” ukus čilija. Pokazano je da se transient receptor potential vanilloid 1 (TRPV1), koji predstavlja jonski kanal prisutan na senzornim neuronima, otvara u prisustvu kapsaicina ili toplote, propuštajući naelektrisane jone kalcijuma u ćeliju. Takav priliv kalcijuma pokreće električne signale koji se šalju u mozak da upozore na toplotu. TRPV1 se nalazi u somatosenzornom sistemu i služi kao multimodalni senzor različitih štetnih stimulusa. Brojne farmakološke i genetičke studije su potvrdile TRPV1 kao terapeutsku metu u nekoliko pretkliničkih modela hroničnog bola, uključujući maligni, neuropatski, postoperativni i mišićno-skeletni bol. Pored toga, ekspresija TRPV1 se takođe primećuje na ne-neuronskim lokalizacijama, kao što su epitel bešike i pluća, ćelije kohlee u uhu. Stoga, lekovi koji mogu da modulišu aktivnost kanala TRPV1 mogu biti korisni za lečenje različitih stanja u rasponu od hroničnog bola do gubitka sluha. Iako je utvrđeno da antagonisti TRPV1 mogu predstavljati važan dodatak terapiji bola, njihova klinička upotreba je i dalje ograničena značajnim neželjenim efektima, kao što je hipertermija. U ovom radu ćemo opisati najvažnije uloge TRPV1 u fiziološkim i patofiziološkim procesima i predstaviti najperspektivnije lekove koji deluju preko TRPV1.The 2021. Nobel Prize in Physiology or Medicine was awarded to scientists who have identified receptors for temperature and touch. In order to conduct this examination, researchers used capsaicin, the compound that gives chili peppers their heat, to discover receptor proteins that allow people to feel chili’s burn. It is shown that transient receptor potential vanilloid 1 (TRPV1), which represents an ion channel present on sensory neurons, opens when it encounters capsaicin or heat, allowing charged calcium ions into the cell. That flood of calcium triggers electrical signals that are sent to the brain to warn of heat. TRPV1 is found in the somatosensory system and serves as a multimodal sensor of different noxious stimuli. Numerous pharmacological and genetic studies have validated TRPV1 as a therapeutic target in several preclinical models of chronic pain, including cancer, neuropathic, postoperative and musculoskeletal pain. Additionally, expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs, cells of the cochlea. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. While antagonists of TRPV1 were found to be a valuable addition to therapy of pain, their clinical use has still been limited by significant side effects, such as hyperthermia. In this review, we will describe the most important roles of TRPV1 in physiological and pathophysiological processes and present the most promising TRPV1-targeted drugs

Evaluation of Prophylactic and Therapeutic Effects of Tramadol and Tramadol Plus Magnesium Sulfate in an Acute Inflammatory Model of Pain and Edema in Rats

Background: Inflammatory pain is the most commonly treated clinical pain, since it develops following trauma or surgery, and accompanies rheumatic or arthritic diseases. Tramadol is one of the most frequently used opioid analgesics in acute and chronic pain of different origin. Magnesium is a widely used dietary supplement that was recently shown to be a safe analgesic drug in different models of inflammatory pain.Aim: This study aimed to evaluate the effects of systemically or locally injected tramadol with/without systemically injected magnesium sulfate in prophylactic or therapeutic protocols of application in a rat model of somatic inflammation.Methods: Inflammation of the rat hind paw was induced by an intraplantar injection of carrageenan (0.1 ml, 0.5%). The antihyperalgesic/antiedematous effects of tramadol (intraperitoneally or intraplantarly injected), and tramadol-magnesium sulfate (subcutaneously injected) combinations were assessed by measuring the changes in paw withdrawal thresholds or paw volume induced by carrageenan. The drugs were administered before or after inflammation induction.Results: Systemically administered tramadol (1.25–10 mg/kg) before or after induction of inflammation reduced mechanical hyperalgesia and edema with a maximal antihyperalgesic/antiedematous effect of about 40–100%. Locally applied tramadol (0.125 mg/paw) better reduced edema (50–100%) than pain (20–50%) during 24 h. Administration of a fixed dose of tramadol (1.25 mg/kg) with different doses of magnesium led to a dose-dependent enhancement and prolongation of the analgesic effect of tramadol both in prevention and treatment of inflammatory pain. Magnesium increases the antiedematous effect of tramadol in the prevention of inflammatory edema while reducing it in treatment.Conclusion: According to results obtained in this animal model, systemic administration of low doses of tramadol and magnesium sulfate given in combination is a potent, effective and relatively safe therapeutic option for prevention and especially therapy of somatic inflammatory pain. The best result is achieved when tramadol is combined with magnesium sulfate at a dose that is equivalent to the average human recommended daily dose and when the drugs are administered when inflammation is maximally developed

μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands

Pharmacotherapy of Rare Diseases in Serbia: The Current State of Art

Rare diseases affect less than 1 in 2000 or 5 in 10,000 people by definition. Most of those diseases have genetic basis (80% of cases) and first symptoms appear in early childhood (50% of cases). Most of these diseases are chronic and degenerative and pharmacotherapy is not available for many of them. Until today, there are more than 7000 rare diseases. In Serbia, the problem of diagnosis and pharmacotherapy of rare diseases is currently under public scrutiny. Patients who suffer from rare diseases in Serbia face many challenges in terms of awareness, timely diagnosis, and adequate treatment. These people are often misdiagnosed or the diagnosis is delayed due to several problems: lack of awareness among medical professionals, lack of expertise, unavailability and/or high costs of diagnostic tests, etc. According to the National Organization of Patients with Rare Diseases in Serbia (NORBS), many diagnostic procedures have to be conducted abroad and the process comprises many difficulties: high costs, travel expenses, or transportation of biological material. Although national legislation ensures the availability of drugs for those diseases, pharmacotherapy is faced with many problems. In this work, we aim to show that improvement of the knowledge regarding rare diseases among both professionals and patients represents a crucial step for enhancement of perspectives for those patients in our community

Cannabinoids and Pain: New Insights From Old Molecules

Cannabis has been used for medicinal purposes for thousands of years. The prohibition of cannabis in the middle of the 20th century has arrested cannabis research. In recent years there is a growing debate about the use of cannabis for medical purposes. The term ‘medical cannabis’ refers to physician-recommended use of the cannabis plant and its components, called cannabinoids, to treat disease or improve symptoms. Chronic pain is the most commonly cited reason for using medical cannabis. Cannabinoids act via cannabinoid receptors, but they also affect the activities of many other receptors, ion channels and enzymes. Preclinical studies in animals using both pharmacological and genetic approaches have increased our understanding of the mechanisms of cannabinoid-induced analgesia and provided therapeutical strategies for treating pain in humans. The mechanisms of the analgesic effect of cannabinoids include inhibition of the release of neurotransmitters and neuropeptides from presynaptic nerve endings, modulation of postsynaptic neuron excitability, activation of descending inhibitory pain pathways, and reduction of neural inflammation. Recent meta-analyses of clinical trials that have examined the use of medical cannabis in chronic pain present a moderate amount of evidence that cannabis/cannabinoids exhibit analgesic activity, especially in neuropathic pain. The main limitations of these studies are short treatment duration, small numbers of patients, heterogeneous patient populations, examination of different cannabinoids, different doses, the use of different efficacy endpoints, as well as modest observable effects. Adverse effects in the short-term medical use of cannabis are generally mild to moderate, well tolerated and transient. However, there are scant data regarding the long-term safety of medical cannabis use. Larger well-designed studies of longer duration are mandatory to determine the long-term efficacy and long-term safety of cannabis/cannabinoids and to provide definitive answers to physicians and patients regarding the risk and benefits of its use in the treatment of pain. In conclusion, the evidence from current research supports the use of medical cannabis in the treatment of chronic pain in adults. Careful follow-up and monitoring of patients using cannabis/cannabinoids are mandatory

Pharmacodynamic evaluation of magnesium sulfate and dizocilpine in models of somatic and visceral pain in rats

Magnezijum je mineral koji u organizmu ima brojne uloge. On je kofaktor u više od 300 enzimskih reakcija, održava membranski potencijal, ima modulatorno dejstvo na jonske kanale, neurotransmisiju, i drugo...Magnesium is a mineral who has many functions in the human body: he is cofactor for 300 enzymatic reaction, modulates ion channels, neurotransmission, etc. Magnesium is an endogenous voltage-dependent N-methyl-D-aspartate (NMDA) receptor channel blocker. Dizocilpine (MK-801) is a noncompetitive NMDA receptor antagonist. Dizocilpine is commonly used as a neuropharmacological tool. The activation of NMDA receptor has a significant role in the development and maintenance of an inflammatory pain. Activation of these receptors may increase the synthesis of nitric oxide (NO). Also, transient receptor potential (TRP) channels and acid sensitive ion channels (ASIC) are important in pain. It is well known that magnesium and dizocilpine can reduce neuropathic pain and enhance analgesic effect of opioids or anesthetics. Aim: The aim of this thesis was to examine whether magnesium sulfate and dizocilpine has analgesic and antiedematous effect in somatic and visceral inflammatory pain in rats and to explore the possible role of NO in the mechanisms of their actions. Methods: Male Wistar rats were used. Carragennan-induced hyperalgesia and edema in rats was used as a model of somatic inflammatory pain. Hyperalgesia was examined by von Fray analgesiometric test. Antiedematous effect was examined by immersing paw in the plethysmometer. The acetic acid-induced writhing test in rats was used as a model of visceral pain. Mechanism of action was evaluated with inhibitors of NOS. Results: In the somatic inflammatory model of pain systemically administered magnesium sulfate reduces hyperalgesia and edema in a dose-independent manner. It is more efficient in lower (5 mg/kg, sc), than in higher doses (15 and 30 mg/kg, sc). The analgesic effect is not present after local peripheral application, as opposed to antiedematous effect that is present after both routes of administration. Magnesium sulfate systematically applied has preventive (given as a pretreatment) and therapeutic (given as treatment) effect on pain and swelling in inflammation. Dizocilpine has dosedependent antihyperalgesic effect after systemical and local peripheral application in the model of somatic inflammation..

Pharmacodynamic evaluation of magnesium sulfate and dizocilpine in models of somatic and visceral pain in rats

Magnezijum je mineral koji u organizmu ima brojne uloge. On je kofaktor u više od 300 enzimskih reakcija, održava membranski potencijal, ima modulatorno dejstvo na jonske kanale, neurotransmisiju, i drugo...Magnesium is a mineral who has many functions in the human body: he is cofactor for 300 enzymatic reaction, modulates ion channels, neurotransmission, etc. Magnesium is an endogenous voltage-dependent N-methyl-D-aspartate (NMDA) receptor channel blocker. Dizocilpine (MK-801) is a noncompetitive NMDA receptor antagonist. Dizocilpine is commonly used as a neuropharmacological tool. The activation of NMDA receptor has a significant role in the development and maintenance of an inflammatory pain. Activation of these receptors may increase the synthesis of nitric oxide (NO). Also, transient receptor potential (TRP) channels and acid sensitive ion channels (ASIC) are important in pain. It is well known that magnesium and dizocilpine can reduce neuropathic pain and enhance analgesic effect of opioids or anesthetics. Aim: The aim of this thesis was to examine whether magnesium sulfate and dizocilpine has analgesic and antiedematous effect in somatic and visceral inflammatory pain in rats and to explore the possible role of NO in the mechanisms of their actions. Methods: Male Wistar rats were used. Carragennan-induced hyperalgesia and edema in rats was used as a model of somatic inflammatory pain. Hyperalgesia was examined by von Fray analgesiometric test. Antiedematous effect was examined by immersing paw in the plethysmometer. The acetic acid-induced writhing test in rats was used as a model of visceral pain. Mechanism of action was evaluated with inhibitors of NOS. Results: In the somatic inflammatory model of pain systemically administered magnesium sulfate reduces hyperalgesia and edema in a dose-independent manner. It is more efficient in lower (5 mg/kg, sc), than in higher doses (15 and 30 mg/kg, sc). The analgesic effect is not present after local peripheral application, as opposed to antiedematous effect that is present after both routes of administration. Magnesium sulfate systematically applied has preventive (given as a pretreatment) and therapeutic (given as treatment) effect on pain and swelling in inflammation. Dizocilpine has dosedependent antihyperalgesic effect after systemical and local peripheral application in the model of somatic inflammation..

Pharmacodynamic evaluation of magnesium sulfate and dizocilpine in models of somatic and visceral pain in rats

Magnezijum je mineral koji u organizmu ima brojne uloge. On je kofaktor u više od 300 enzimskih reakcija, održava membranski potencijal, ima modulatorno dejstvo na jonske kanale, neurotransmisiju, i drugo...Magnesium is a mineral who has many functions in the human body: he is cofactor for 300 enzymatic reaction, modulates ion channels, neurotransmission, etc. Magnesium is an endogenous voltage-dependent N-methyl-D-aspartate (NMDA) receptor channel blocker. Dizocilpine (MK-801) is a noncompetitive NMDA receptor antagonist. Dizocilpine is commonly used as a neuropharmacological tool. The activation of NMDA receptor has a significant role in the development and maintenance of an inflammatory pain. Activation of these receptors may increase the synthesis of nitric oxide (NO). Also, transient receptor potential (TRP) channels and acid sensitive ion channels (ASIC) are important in pain. It is well known that magnesium and dizocilpine can reduce neuropathic pain and enhance analgesic effect of opioids or anesthetics. Aim: The aim of this thesis was to examine whether magnesium sulfate and dizocilpine has analgesic and antiedematous effect in somatic and visceral inflammatory pain in rats and to explore the possible role of NO in the mechanisms of their actions. Methods: Male Wistar rats were used. Carragennan-induced hyperalgesia and edema in rats was used as a model of somatic inflammatory pain. Hyperalgesia was examined by von Fray analgesiometric test. Antiedematous effect was examined by immersing paw in the plethysmometer. The acetic acid-induced writhing test in rats was used as a model of visceral pain. Mechanism of action was evaluated with inhibitors of NOS. Results: In the somatic inflammatory model of pain systemically administered magnesium sulfate reduces hyperalgesia and edema in a dose-independent manner. It is more efficient in lower (5 mg/kg, sc), than in higher doses (15 and 30 mg/kg, sc). The analgesic effect is not present after local peripheral application, as opposed to antiedematous effect that is present after both routes of administration. Magnesium sulfate systematically applied has preventive (given as a pretreatment) and therapeutic (given as treatment) effect on pain and swelling in inflammation. Dizocilpine has dosedependent antihyperalgesic effect after systemical and local peripheral application in the model of somatic inflammation..