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1.
Molecules ; 27(4)2022 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-35209126

RESUMO

P2X3 receptors (P2X3R) are ATP-gated ion channels predominantly expressed in C- and Aδ-fiber primary afferent neurons and have been introduced as a novel therapeutic target for neurological disorders, including neuropathic pain and chronic cough. Because of its localized distribution, antagonism of P2X3R has been thoroughly considered, and the avoidance of issues related to CNS side effects has been proven in clinical trials. In this article, benzimidazole-4,7-dione-based derivatives were introduced as a new chemical entity for the development of P2X3R antagonists. Starting from the discovery of a hit compound from the screening of 8364 random library compounds in the Korea Chemical Bank, which had an IC50 value of 1030 nM, studies of structure-activity and structure-property relationships enabled further optimization toward improving the antagonistic activities as well as the drug's physicochemical properties, including metabolic stability. As for the results, the final optimized compound 14h was developed with an IC50 value of 375 nM at P2X3R with more than 23-fold selectivity versus P2X2/3R, along with properties of metabolic stability and improved solubility. In neuropathic pain animal models evoked by either nerve ligation or chemotherapeutics in male Sprague-Dawley rats, compound 14h showed anti-nociceptive effects through an increase in the mechanical withdrawal threshold as measured by von Frey filament following intravenous administration.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/farmacologia , Analgésicos/síntese química , Animais , Benzimidazóis/síntese química , Técnicas de Química Sintética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Monitoramento de Medicamentos , Humanos , Camundongos , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2X/síntese química , Ratos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
2.
Pharmacology ; 105(3-4): 173-180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31578020

RESUMO

BACKGROUND: Chemotherapy-induced neuropathic pain (CINP) is a serious side effect of chemotherapy. Korean Red Ginseng (KRG) is a popular herbal medicine in Asian countries. We examined the therapeutic potential of intrathecally administered KRG for CINP and clarified the mechanisms of action with regard to 5-hydroxytryptamine (5-HT)7 receptor at the spinal level. METHODS: CINP was evoked by intraperitoneal injection of cisplatin in male Sprague-Dawley rats. After examining the effects of intrathecally administered KRG on CINP, 5-HT receptor antagonist (dihydroergocristine [DHE]) was pretreated to determine the involvement of 5-HT receptor. In addition, intrathecal 5-HT7 receptor antagonist (SB269970) was administered to define the role of 5-HT7 receptor on the effect of KRG. 5-HT7 receptor mRNA expression levels and 5-HT concentrations were examined in the spinal cord. RESULTS: Intrathecally administered KRG produced a limited, but a dose-dependent, antiallodynic effect. Intrathecally administered DHE antagonized the antiallodynia caused by KRG. Furthermore, intrathecal SB269970 also reversed the effect of KRG. No changes in 5-HT7 receptor mRNA expression were seen in the dorsal horn of the spinal cord after cisplatin injection. After injecting cisplatin, 5-HT levels were decreased in the spinal cord, whereas those of 5-HT were increased by intrathecal KRG. CONCLUSIONS: Intrathecally administered KRG decreased CINP. In addition, spinal 5-HT7 receptors contributed to the antiallodynic effect of KRG.


Assuntos
Cisplatino/toxicidade , Neuralgia/prevenção & controle , Panax/química , Extratos Vegetais/farmacologia , Animais , Antineoplásicos/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Injeções Espinhais , Masculino , Neuralgia/induzido quimicamente , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
3.
ChemMedChem ; 14(20): 1783-1794, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31359587

RESUMO

Gi -protein-biased agonists with minimal ß-arrestin recruitment represent opportunities to overcome the serious adverse effects of human mu opioid receptor (µ-OR) agonists and developing alternative and safe treatments for pain. In order to discover novel non-morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in-house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel µ-OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R-group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new Gi -protein-biased compound, 1-{5-(3-chlorophenyl)-7,8-dimethoxy-3-[4-(methylsulfonyl)benzyl]-3H-pyrazolo[3,4-c]isoquinolin-1-yl}-N,N-dimethylmethanamine, showed an EC50 value of 179 nm against the µ-OR. This resulted in significant pain relief for mice in the phase II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G-protein-coupled receptors.


Assuntos
Analgésicos Opioides/farmacologia , Descoberta de Drogas , Metilaminas/farmacologia , Dor/tratamento farmacológico , Receptores Opioides mu/agonistas , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Formaldeído/administração & dosagem , Humanos , Ligantes , Metilaminas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Dor/induzido quimicamente , Ratos , Relação Estrutura-Atividade
4.
BMC Complement Altern Med ; 16: 214, 2016 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-27411500

RESUMO

BACKGROUND: For their analgesic and anti-arthritic effects, Aconitum species have been used in folk medicine in some East Asian countries. Although their analgesic effect is attributed to its action on voltage-dependent sodium channels, they also suppress purinergic receptor expression in dorsal root ganglion neurons in rats with neuropathic pain. In vitro study also demonstrated that the Aconitum suppresses ATP-induced P2X7 receptor (P2X7R)-mediated inflammatory responses in microglial cell lines. Herein, we examined the effect of intrathecal administration of thermally processed Aconitum jaluense (PA) on pain behavior, P2X7R expression and microglial activation in a rat spinal nerve ligation (SNL) model. METHODS: Mechanical allodynia induced by L5 SNL in Sprague-Dawley rats was measured using the von Frey test to evaluate the effect of intrathecal injection of PA. Changes in the expression of P2X7R in the spinal cord were examined using RT-PCR and Western blot analysis. In addition, the effect of intrathecal PA on microglial activation was evaluated by immunofluorescence. RESULTS: Intrathecal PA attenuated mechanical allodynia in a dose-dependent manner showing both acute and chronic effects with 65 % of the maximal possible effect. The expression and production of spinal P2X7R was increased five days after SNL, but daily intrathecal PA injection significantly inhibited the increase to the level of naïve animals. Immunofluorescence of the spinal cord revealed a significant increase in P2X7R expression and activation of microglia in the dorsal horn, which was inhibited by intrathecal PA treatment. P2X7R co-localized with microglia marker, but not neurons. CONCLUSIONS: Intrathecal PA exerts anti-allodynic effects in neuropathic pain, possibly by suppressing P2X7R production and expression as well as reducing microglial activation in the spinal cord.


Assuntos
Aconitum/química , Analgésicos/farmacologia , Hiperalgesia/metabolismo , Microglia/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Medula Espinal/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo
5.
J Altern Complement Med ; 16(12): 1285-90, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21138388

RESUMO

OBJECTIVES: Controversy exists regarding the efficacy of ligament prolotherapy in alleviating sacroiliac joint pain. The inconsistent success rates reported in previous studies may be attributed to variability in patient selection and techniques between studies. It was hypothesized that intra-articular prolotherapy for patients with a positive response to diagnostic block may mitigate the drawbacks of ligament prolotherapy. The purpose of this study was to evaluate the efficacy and long-term effectiveness of intra-articular prolotherapy in relieving sacroiliac joint pain, compared with intra-articular steroid injection. DESIGN: This was a prospective, randomized, controlled trial. SETTINGS/LOCATION: The study was conducted at an outpatient pain medicine clinic at Chonnam National University Hospital in Gwang-ju, Korea. SUBJECTS: The study included patients with sacroiliac joint pain, confirmed by ≥50% improvement in response to local anesthetic block, lasting 3 months or longer, and who failed medical treatment. INTERVENTIONS: The treatment involved intra-articular dextrose water prolotherapy or triamcinolone acetonide injection using fluoroscopic guidance, with a biweekly schedule and maximum of three injections. OUTCOME MEASURES: Pain and disability scores were assessed at baseline, 2 weeks, and monthly after completion of treatment. RESULTS: The numbers of recruited patients were 23 and 25 for the prolotherapy and steroid groups, respectively. The pain and disability scores were significantly improved from baseline in both groups at the 2-week follow-up, with no significant difference between them. The cumulative incidence of ≥50% pain relief at 15 months was 58.7% (95% confidence interval [CI] 37.9%-79.5%) in the prolotherapy group and 10.2% (95% CI 6.7%-27.1%) in the steroid group, as determined by Kaplan-Meier analysis; there was a statistically significant difference between the groups (log-rank p < 0.005). CONCLUSIONS: Intra-articular prolotherapy provided significant relief of sacroiliac joint pain, and its effects lasted longer than those of steroid injections. Further studies are needed to confirm the safety of the procedure and to validate an appropriate injection protocol.


Assuntos
Anti-Inflamatórios/uso terapêutico , Terapias Complementares , Glucocorticoides/uso terapêutico , Glucose/uso terapêutico , Dor Lombar/tratamento farmacológico , Triancinolona/uso terapêutico , Idoso , Feminino , Glucose/administração & dosagem , Humanos , Injeções Intra-Articulares/métodos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Articulação Sacroilíaca
6.
Korean J Pain ; 23(4): 230-5, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21217885

RESUMO

BACKGROUND: Bone cancer pain has a disruptive effect on the cancer patient's quality of life. Although ginsenosides have been used as traditional medicine in Eastern Medicine, the effect on bone cancer pain has not been thoroughly studied. The aim of this study was to determine whether ginsenosides may alter the bone cancer pain at the spinal level. METHODS: NCTC 2472 tumor cells (2.5 × 10(5)) were injected into the femur of adult male C3H/HeJ mice to evoke bone tumor and bone cancer pain. To develop bone tumor, radiologic pictures were obtained. To assess pain, the withdrawal threshold was measured by applying a von Frey filament to the tumor cells inoculation site. The effect of intrathecal ginsenosides was investigated. Effect of ginsenosides (150, 500, 1,000 µg) was examined at 15, 30, 60, 90, 120 min after intrathecal delivery. RESULTS: The intrafemoral injection of NCTC 2472 tumor cells induced a radiological bone tumor. The withdrawal threshold with tumor development was significantly decreased compared to the sham animals. Intrathecal ginsenosides effectively increased the withdrawal threshold in the bone cancer site. CONCLUSIONS: NCTC 2472 tumor cells injection into the mice femur caused bone tumor and bone cancer pain. Intrathecal ginsenosides attenuated the bone cancer-related pain behavior. Therefore, spinal ginsenosides may be an alternative analgesic for treating bone cancer pain.

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