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1.
Eur J Med Chem ; 177: 269-290, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158744

RESUMO

Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC50 = 3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole) were evaluated in comparison to MY 5445 (4b) in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment.


Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Ftalazinas/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores da Fosfodiesterase 5/síntese química , Inibidores da Fosfodiesterase 5/química , Ftalazinas/síntese química , Ftalazinas/química , Solubilidade , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 174: 226-235, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042618

RESUMO

A new set of 5-chlorobenzoxazole- and 5-chlorobenzothiazole-based derivatives containing the azepane ring as a basic moiety was designed, synthesized and evaluated through binding assays to measure their affinity and selectivity towards σ1 and σ2 receptors. Compounds 19, 22 and 24, with a four units spacer between the bicyclic scaffold and the azepane ring, showed nanomolar affinity towards both receptor subtype and the best Ki values (Ki σ1 = 1.27, 2.30, and 0.78 and Ki σ2 = 7.9, 3.8, and 7.61 nM, respectively). Evaluation of cytotoxic and apoptotic effects in MCF-7 human cancer cells was useful to assess σ2 receptor activity, while an in vivo mice model of inflammatory pain allowed to analyze σ1 receptor pharmacological properties. In vitro and in vivo results suggested that compound 19 is a σ1/σ2 agonist, compound 24 a σ1 antagonist/σ2 agonist, whereas compound 22 might act as σ1 antagonist/σ2 partial agonist. Due to their pharmacological profile, a potential therapeutic application in cancer of aforesaid novel σ1/σ2 receptor ligands, especially 22 and 24, is proposed.


Assuntos
Analgésicos/uso terapêutico , Benzotiazóis/uso terapêutico , Benzoxazóis/uso terapêutico , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Humanos , Ligantes , Células MCF-7 , Camundongos , Estrutura Molecular
3.
Eur J Med Chem ; 177: 47-62, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129453

RESUMO

The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in ß- or γ-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in γ-position possess higher GluN2B affinity than analogs bearing the F-atom in ß-position. This effect was attributed to the reduced basicity of ß-fluoro amines. 3-Benzazepines with a benzylic OH moiety show moderate GluN2B affinity, but considerable selectivity over the σ2 receptor. However, removal of the benzylic OH moiety led to increased GluN2B affinity, but reduced GluN2B/σ2 selectivity. With respect to GluN2B affinity the phenol 17b with a γ-fluorophenylbutyl moiety in 3-position represents the most interesting fluorinated ligand (Ki(GluN2B) = 16 nM). Most of the synthesized ligands reveal either similar GluN2B and σ1 affinity or higher σ1 affinity than GluN2B affinity. The methyl ether 16b shows high σ1 affinity (Ki(σ1) = 6.6 nM) and high selectivity over a broad panel of receptors and transporters. The high antiallodynic activity in the mouse capsaicin assay proved the σ1 antagonistic activity of 16b.


Assuntos
Analgésicos/uso terapêutico , Benzazepinas/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hiperalgesia/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores sigma/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Analgésicos/toxicidade , Animais , Benzazepinas/síntese química , Benzazepinas/química , Benzazepinas/toxicidade , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Humanos , Ligantes , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piperidinas/uso terapêutico , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 177: 188-197, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136893

RESUMO

Carbonic Anhydrases have been recently validated as novel therapeutic targets in neuropathic pain. In this study, we combine the anticonvulsant propriety of spyrohydantoin and the CA inhibitor moiety of benzenesulfonamide to synthesize a novel series of spyrohydantoin bearing sulfonamides with strong activity against hCA II and VII. These isoforms are present in the nervous system and largely expressed both at the central as well as at peripheral level and can be modulated for pain relief. The crystal structures of hCA II in complex with selected compounds 5a-c demonstrate the importance of the tail in the binding modes within the isoform. Finally, in vivo, in an animal model of oxaliplatin induced neuropathy, compounds with organoselenium tails (8b-c) showed potent neuropathic pain attenuating effects. Taken together, these data strongly suggest the translational utility of these inhibitors as novel pain relievers.


Assuntos
Analgésicos/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Hidantoínas/uso terapêutico , Neuralgia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Cristalografia por Raios X , Desenho de Drogas , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Masculino , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
5.
Eur J Med Chem ; 176: 310-325, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31112892

RESUMO

A series of compounds generated by ring expansion/opening and molecular elongation/simplification of the 1,3-dioxolane scaffold were prepared and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compounds with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate (12) emerged as highly potent full agonist at the 5-HT1AR (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 92). The pharmacokinetic data in rats showed that the orally administered 12 has a high biodistribution in the brain compartment. Thus, 12 was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, 12 was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain.


Assuntos
Analgésicos/uso terapêutico , Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Dioxanos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Analgésicos/síntese química , Analgésicos/farmacocinética , Analgésicos/toxicidade , Animais , Ansiolíticos/síntese química , Ansiolíticos/farmacocinética , Ansiolíticos/toxicidade , Antidepressivos/síntese química , Antidepressivos/farmacocinética , Antidepressivos/toxicidade , Encéfalo/metabolismo , Dioxanos/síntese química , Dioxanos/farmacocinética , Dioxanos/toxicidade , Masculino , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/toxicidade , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/síntese química , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT1 de Serotonina/toxicidade , Estereoisomerismo , Relação Estrutura-Atividade
6.
An Acad Bras Cienc ; 90(1 Suppl 2): 1073-1088, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29873669

RESUMO

N-acylhydrazone is an interesting privileged structure that has been used in the molecular design of a myriad of bioactive compounds. In order to identify new antinociceptive drug candidates, we described herein the design, synthesis, X-ray diffraction study and the pharmacological evaluation of a series of 3-amino-4-methylthiophene-2-acylcarbohydrazone derivatives (8a-t). Compounds were prepared in good overall yields through divergent synthesis from a common key intermediate and were characterized by classical spectroscopy methods. X-ray diffraction study was employed for unequivocal determination of the imine double bond stereochemistry. 8a-t were evaluated in vivo through oral administration using the classical writhing test in mice. N-acylhydrazone derivatives 8j and 8l displayed relative potency similar to dipyrone, highlighting them as promising analgesic lead-candidates for further investigation.


Assuntos
Analgésicos/síntese química , Anti-Inflamatórios/síntese química , Hidrazonas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Desenho de Drogas , Hidrazonas/farmacologia , Espectrometria de Massas , Camundongos , Difração de Raios X
7.
Molecules ; 23(6)2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29882911

RESUMO

A new series of 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N′-[(E)-(substituted phenyl) methylidene] acetohydrazide derivatives (S1⁻S18) were synthesized and evaluated for their anti-inflammatory activity, analgesic activity, ulcerogenic activity, lipid peroxidation, ulcer index and cyclooxygenase expression activities. All the synthesized compounds were in good agreement with spectral and elemental analysis. Three synthesized compounds (S3, S7 and S14) have shown significant anti-inflammatory activity as compared to the reference drug indomethacin. Compound S3 was further tested for ulcerogenic index and cyclooxygenase (COX) expression activity. It was selectively inhibiting COX-2 expression and providing the gastric sparing activity. Docking studies have revealed the potential of these compounds to bind with COX-2 enzyme. Compound S3 formed a hydrogen bond between OH of Tyr 355 and NH2 of Arg 120 with carbonyl group and this hydrogen bond was similar to that formed by indomethacin. This study provides insight for compound S3, as a new lead compound as anti-inflammatory agent and selective COX-2 inhibitor.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Indóis/química , Indóis/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores de Ciclo-Oxigenase 2/síntese química , Avaliação Pré-Clínica de Medicamentos , Ligações de Hidrogênio , Indóis/síntese química , Masculino , Espectrometria de Massas , Camundongos , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Ratos
8.
Eur J Med Chem ; 154: 233-252, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29803996

RESUMO

Fatty acid binding proteins (FABPs) serve as critical modulators of endocannabinoid signaling by facilitating the intracellular transport of anandamide and whose inhibition potentiates anandamide signaling. Our previous work has identified a novel small-molecule FABP inhibitor, α-truxillic acid 1-naphthyl monoester (SB-FI-26, 3) that has shown efficacy as an antinociceptive and anti-inflammatory agent in rodent models. In the present work, we have performed an extensive SAR study on a series of 3-analogs as novel FABP inhibitors based on computer-aided inhibitor drug design and docking analysis, chemical synthesis and biological evaluations. The prediction of binding affinity of these analogs to target FABP3, 5 and 7 isoforms was performed using the AutoDock 4.2 program, using the recently determined co-crystal structures of 3 with FABP5 and FABP7. The compounds with high docking scores were synthesized and evaluated for their activities using a fluorescence displacement assay against FABP3, 5 and 7. During lead optimization, compound 3l emerged as a promising compound with the Ki value of 0.21 µM for FABP 5, 4-fold more potent than 3 (Ki, 0.81 µM). Nine compounds exhibit similar or better binding affinity than 3, including compounds 4b (Ki, 0.55 µM) and 4e (Ki, 0.68 µM). Twelve compounds are selective for FABP5 and 7 with >10 µM Ki values for FABP3, indicating a safe profile to avoid potential cardiotoxicity concerns. Compounds 4f, 4j and 4k showed excellent selectivity for FABP5 and would serve as other new lead compounds. Compound 3a possessed high affinity and high selectivity for FABP7. Compounds with moderate to high affinity for FABP5 displayed antinociceptive effects in mice while compounds with low FABP5 affinity lacked in vivo efficacy. In vivo pain model studies in mice revealed that exceeding hydrophobicity significantly affects the efficacy. Thus, among the compounds with high affinity to FABP5 in vitro, the compounds with moderate hydrophobicity were identified as promising new lead compounds for the next round of optimization, including compounds 4b and 4j. For select cases, computational analysis of the observed SAR, especially the selectivity of new inhibitors to particular FABP isoforms, by comparing docking poses, interaction map, and docking energy scores has provided useful insights.


Assuntos
Analgésicos/farmacologia , Ciclobutanos/farmacologia , Ésteres/farmacologia , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Animais , Projeto Auxiliado por Computador , Ciclobutanos/síntese química , Ciclobutanos/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Ésteres/síntese química , Ésteres/química , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
9.
Mini Rev Med Chem ; 18(17): 1452-1478, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29663882

RESUMO

Nitrogen and sulphur based heterocyclic molecules have gained significant attention owing to their broad spectrum pharmacological profiles. Thiazine is one of such promising scaffolds which has been widely utilized in the synthesis of compounds that possess interesting biological profile including anti-proliferative, anti-bacterial, antipsychotic, analgesic, anti-inflammatory, antifungal and antiviral activities. The current review focuses on the chemistry of thiazine and its derivatives along with potential pharmacological activities reported for these in scientific literature. Multifaceted pharmacological profile of thiazine derivatives provides new aspects for the design of superior medicinally active agents.


Assuntos
Tiazinas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/química , Antipsicóticos/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Humanos , Estrutura Molecular , Tiazinas/síntese química , Tiazinas/química
10.
Chin J Nat Med ; 16(3): 231-240, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29576060

RESUMO

Novel series of limonin derivatives (V-A-1-V-A-8, V-B-1-V-B-8) were synthesized by adding various tertiary amines onto the C (7)-position of limonin. The synthesized compounds possessed favorable physicochemical property, and the intrinsic solubility of the novel compounds were significantly improved, compared with limonin. Different pharmacological models were used to evaluate the analgesic and anti-inflammatory activities of the target compounds. Compound V-A-8 exhibited the strongest in vivo activity among the novel limonin analogs; its analgesic activity was more potent than aspirin and its anti-inflammatory activity was stronger than naproxen under our testing conditions.


Assuntos
Analgésicos/química , Anti-Inflamatórios/química , Limoninas/química , Analgésicos/administração & dosagem , Analgésicos/síntese química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/síntese química , Descoberta de Drogas , Edema/tratamento farmacológico , Humanos , Limoninas/administração & dosagem , Limoninas/síntese química , Camundongos , Estrutura Molecular , Dor/tratamento farmacológico
11.
Drug Discov Today ; 23(8): 1520-1529, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29567427

RESUMO

N-acylethanolamines (NAEs) (e.g., N-palmitoylethanolamine, N-arachidonoylethanolamine, N-oleoylethanolamine) are bioactive lipids involved in many physiological processes including pain, inflammation, anxiety, cognition and food intake. Two enzymes are responsible for the hydrolysis of NAEs and therefore regulate their endogenous levels and effects: fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA). As discussed here, extensive biochemical characterization of NAAA was carried out over the years that contributed to a better understanding of NAAA enzymology. An increasing number of studies describe the synthesis and pharmacological characterization of NAAA inhibitors. Recent medicinal chemistry efforts have led to the development of potent and stable inhibitors that enable studying the effects of NAAA inhibition in preclinical disease models, notably in the context of pain and inflammation.


Assuntos
Amidoidrolases/antagonistas & inibidores , Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Amidoidrolases/metabolismo , Analgésicos/síntese química , Animais , Anti-Inflamatórios/síntese química , Inibidores Enzimáticos/síntese química , Etanolaminas/metabolismo , Humanos , Hidrólise , Conformação Proteica , Relação Estrutura-Atividade
12.
Chin J Nat Med ; 16(2): 113-124, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29455726

RESUMO

Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC50 120 nmol·L-1) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.


Assuntos
Analgésicos/administração & dosagem , Analgésicos/síntese química , Dor Crônica/tratamento farmacológico , Diterpenos de Abietano/administração & dosagem , Diterpenos de Abietano/síntese química , Analgésicos/química , Animais , Dor Crônica/enzimologia , Diterpenos de Abietano/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Relação Estrutura-Atividade
13.
J Enzyme Inhib Med Chem ; 33(1): 405-415, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29372659

RESUMO

Twelve new derivatives of benzothiazole bearing benzenesulphonamide and carboxamide were synthesised and investigated for their in vivo anti-inflammatory, analgesic and ulcerogenic activities. Molecular docking showed an excellent binding interaction of the synthesised compounds with the receptors, with 17c showing the highest binding energy (-12.50 kcal/mol). Compounds 17c and 17i inhibited carrageenan-induced rat paw oedema at 72, 76, and 80% and 64, 73, and 78% at 1 h, 2 h, and 3 h, respectively. In the analgesic activity experiment, compounds 17c, 17 g, and 17i had ED50 (µM/kg) of 96, 127, and 84 after 0.5 h; 102, 134, and 72 after 1 h and 89, 156, and 69 µM/kg after 2 h, respectively, which were comparable with 156, 72, and 70 µM/kg for celecoxib. The ulcerogenic index of the most active derivatives 17c and 17i were 0.82 and 0.89, respectively, comparable to 0.92 for celecoxib. The physicochemical studies of the new derivatives showed that they will not have oral bioavailability problems.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Benzotiazóis/farmacologia , Simulação de Acoplamento Molecular , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Edema/tratamento farmacológico , Masculino , Camundongos , Estrutura Molecular , Ratos , Úlcera/induzido quimicamente , Úlcera/tratamento farmacológico
14.
Med Chem ; 14(4): 356-371, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29332598

RESUMO

BACKGROUND: Isoxazoles, pyridazines, and pyrimidopyrazines have recently attracted attention due to their potent pharmacological activities. They exhibited anticancer, neuroprotective, analgesic and anti-inflammatory effects. OBJECTIVE: The study aimed to synthesize novel isoxazoles, pyridazines, and pyrimidopyrazines through efficient high yield protocol for evaluating their analgesics and anti-inflammatory activities. METHOD: A series of novel isoxazole-, pyridazine-, pyrimidopyrazine derivatives was prepared from 5,8-alkyl-1,3-dimethyl-5,6-dihydropyrimido[5,6-e]pyrazine-2,4,7-trione (1a,b) as the starting material. RESULTS: The prepared derivatives were synthesized in moderate to good yields (60-75%) in a stepwise efficient protocol under mild condition. These new compounds have been proven by several spectroscopic techniques as IR, 1D and 2D NMR techniques and mass analysis. The in vivo anti-inflammatory was assessed for the synthesized compounds using carrageenan-induced rat hind paw edema model. Also, the in vivo analgesic activity for these products was examined utilizing hot-plate and acetic acid-induced writhing response assays. CONCLUSION: The isoxazole derivatives (3a-f) showed the most forceful anti-inflammatory and analgesic activities. Pyrimidopyrazines (4a-f) demonstrated weaker but comparable antiinflammatory and analgesic activities to the positive controls.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Isoxazóis/farmacologia , Pirazinas/farmacologia , Piridazinas/farmacologia , Pirimidinas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Avaliação Pré-Clínica de Medicamentos , Feminino , Isoxazóis/síntese química , Isoxazóis/química , Masculino , Camundongos , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Piridazinas/síntese química , Piridazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos Sprague-Dawley
15.
Sci Rep ; 8(1): 1004, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343689

RESUMO

We here describe a novel α-conopeptide, Eu1.6 from Conus eburneus, which exhibits strong anti-nociceptive activity by an unexpected mechanism of action. Unlike other α-conopeptides that largely target nicotinic acetylcholine receptors (nAChRs), Eu1.6 displayed only weak inhibitory activity at the α3ß4 and α7 nAChR subtypes and TTX-resistant sodium channels, and no activity at TTX-sensitive sodium channels in rat dorsal root ganglion (DRG) neurons, or opiate receptors, VR1, KCNQ1, L- and T-type calcium channels expressed in HEK293 cells. However, Eu1.6 inhibited high voltage-activated N-type calcium channel currents in isolated mouse DRG neurons which was independent of GABAB receptor activation. In HEK293 cells expressing CaV2.2 channels alone, Eu1.6 reversibly inhibited depolarization-activated Ba2+ currents in a voltage- and state-dependent manner. Inhibition of CaV2.2 by Eu1.6 was concentration-dependent (IC50 ~1 nM). Significantly, systemic administration of Eu1.6 at doses of 2.5-5.0 µg/kg exhibited potent analgesic activities in rat partial sciatic nerve injury and chronic constriction injury pain models. Furthermore, Eu1.6 had no significant side-effect on spontaneous locomotor activity, cardiac and respiratory function, and drug dependence in mice. These findings suggest α-conopeptide Eu1.6 is a potent analgesic for the treatment of neuropathic and chronic pain and opens a novel option for future analgesic drug design.


Assuntos
Analgésicos/farmacologia , Canais de Cálcio Tipo N/metabolismo , Dor Crônica/tratamento farmacológico , Conotoxinas/farmacologia , Peptídeos/farmacologia , Neuropatia Ciática/tratamento farmacológico , Sequência de Aminoácidos , Analgésicos/síntese química , Analgésicos/isolamento & purificação , Animais , Cálcio/metabolismo , Dor Crônica/metabolismo , Dor Crônica/fisiopatologia , Conotoxinas/síntese química , Conotoxinas/isolamento & purificação , Caramujo Conus/química , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Células HEK293 , Humanos , Injeções Intramusculares , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Técnicas de Patch-Clamp , Peptídeos/síntese química , Peptídeos/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/metabolismo , Neuropatia Ciática/fisiopatologia , Técnicas de Síntese em Fase Sólida , Xenopus laevis
16.
Bioorg Med Chem ; 26(1): 257-265, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29208511

RESUMO

Lysophosphatidic acid (LPA) plays an important role in a variety of cellular functions. In particular, LPA5 receptor is highly expressed in spinal cord and dorsal root ganglion, which are associated with pain. This fact prompted us to hypothesize that LPA5 antagonists show analgesic effects. To search for potent LPA5 antagonists with blood brain barrier (BBB) permeability, we conducted high throughput screening (HTS). In HTS campaign, we found a 2H-isoquinoline-1-one scaffold showing antagonistic activity against LPA5 and synthesized a series of 2H-isoquinoline-1-one derivatives and evaluated their LPA5 activities. Among these compounds, compound 7e showed potent LPA5 activity with an IC50 value of 0.12 µM, and acceptable BBB permeability. Furthermore, it showed effective analgesic effect in a chronic constriction injury rat model. Therefore, 7e may have a potential as novel pain therapeutic approach.


Assuntos
Analgésicos/farmacologia , Constrição Patológica/tratamento farmacológico , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Analgésicos/síntese química , Analgésicos/química , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 143: 157-165, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29174812

RESUMO

α7 Nicotinic acetylcholine receptors (nAChRs) are ion channels implicated in a number of CNS pathological processes, including pain and psychiatric, cognitive and inflammatory diseases. Comparing with orthosteric agonism, positive allosteric modulation of these channels constitutes an interesting approach to achieve selectivity versus other nicotinic receptors. We have recently described new chalcones and 1,3-diphenylpropanones as positive allosteric modulators (PAMs) of α7 nAChRs, which proved to have good analgesic activities but poor pharmacokinetic properties. Here we report the preparation of amino acid and peptide derivatives as prodrugs of these modulators with the aim of improving their in vivo biological activity. While the valine derivative showed very short half life in aqueous solutions to be considered a prodrug, Val-Val and Val-Pro-Val are suitable precursors of the parent 1,3-diphenylpropanones, via chemical and enzymatic transformation, respectively. Compounds 19 (Val-Val) and 21 (Val-Pro-Val), prodrugs of the 2',5',4-trihydroxy-1,3-diphenylpropan-1-one 3, showed significant antinociceptive activity in in vivo assays. The best compound, 21, displayed a better profile in the analgesia test than its parent compound 3, exhibiting about the same potency but long-lasting effects.


Assuntos
Aminoácidos/farmacologia , Analgésicos/farmacologia , Dor/tratamento farmacológico , Peptídeos/farmacologia , Fenilpropionatos/farmacologia , Pró-Fármacos/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Regulação Alostérica/efeitos dos fármacos , Aminoácidos/síntese química , Aminoácidos/química , Analgésicos/síntese química , Analgésicos/química , Animais , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Adjuvante de Freund , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Estrutura Molecular , Medição da Dor , Peptídeos/síntese química , Peptídeos/química , Fenilpropionatos/síntese química , Fenilpropionatos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Xenopus
18.
Artif Cells Nanomed Biotechnol ; 46(1): 138-146, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28323508

RESUMO

Once-daily oral dosage of nefopam hydrochloride loaded sustained release microspheres (NPH-MS) was investigated as novel therapeutic strategy for post-operative pain management. Microspheres were synthesized using poly-3-hydroxybutyrate and poly-(ɛ-caprolactone) by double emulsion solvent evaporation technique. NPH-MS were characterized through FTIR, PXRD and SEM. In-vitro drug release study revealed sustained behavior till 24 h. Haemolysis was <5% which signified haemocompatibility of formulation. ED50 in rat tail-flick anti-nociceptive test was found ∼18.12 mg/kg. In post-operative pain model, reversal of mechanical allodynia and thermal hyperalgesia by NPH-MS was statistically significant (p < .001) as compared with NPH till 24 h post-dose.


Assuntos
Fenômenos Químicos , Portadores de Fármacos/química , Microesferas , Nefopam/química , Nefopam/farmacologia , Dor Pós-Operatória/tratamento farmacológico , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Técnicas de Química Sintética , Liberação Controlada de Fármacos , Hemólise/efeitos dos fármacos , Humanos , Hidroxibutiratos/química , Hiperalgesia/tratamento farmacológico , Teste de Materiais , Nefopam/síntese química , Nefopam/uso terapêutico , Poliésteres/química , Ratos
19.
Mini Rev Med Chem ; 18(3): 216-233, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28137242

RESUMO

1,3,4-Oxadiazole derivatives are found to have a wide range of pharmacological activities and attracting the researchers to work on this nucleus. Literature survey indicates that many 1,3,4- oxadiazoles have been synthesized with the aim to get compounds of significant anti-inflammatory and analgesic activities with reduced adverse effects. The purpose of this review is to compile the reports on 1,3,4-oxadiazole derivatives possessing anti-inflammatory and analgesic activities. The review also includes the reports on 1,3,4-oxadiazole derivatives of existing NSAIDs in the last ten years.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Inflamação/tratamento farmacológico , Oxidiazóis/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Humanos , Estrutura Molecular , Oxidiazóis/química
20.
Med Chem ; 14(3): 269-280, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28641526

RESUMO

BACKGROUND: Serious side effects such as gastric intestinal ulcer, bleeding etc. are associated with most of the antiinflammatory and analgesic drugs. So, there is a need to search novel, potent, and safer antiinflammatory and analgesic drug. METHOD: Based on "biology-oriented synthesis approach", piperine alkaloid was isolated from Piper nigrum L. and some derivatives of piperine having azomethine, sulfamoyl, propanoyl, acetamoyl and heterocyclic oxadiazole were synthesized. The structures of synthetic derivatives were confirmed by using different spectroscopic techniques such as 1H-, 13C-NMR, EI-MS, and IR. Melting points were also determined for all compounds. Piperine and its all the synthetic derivatives were subjected to comparative in vivo evaluation of analgesic and antiinflammatory activities at the oral dose of 6 mg/kg/day. Analgesic activity was evaluated by tail immersion, hot plate and acetic acid writhing methods. While, antiinflammatory activity was evaluated by carrageenan-induced paw inflammation. In silico studies of all synthetic compounds was also conducted on COX-2 and adenosine kinase enzymes. RESULTS: A number of derivatives showed enhanced antiinflammatory and analgesic activities as compared to piperine and standard drug diclofenac. CONCLUSION: The newly identified molecules may serve as lead for the future research in connection of potent and safer antiinflammatory and analgesic drug candidate.


Assuntos
Alcaloides/farmacologia , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Benzodioxóis/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Adenosina Quinase/antagonistas & inibidores , Alcaloides/síntese química , Alcaloides/química , Alcaloides/isolamento & purificação , Analgésicos/síntese química , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Benzodioxóis/síntese química , Benzodioxóis/química , Benzodioxóis/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/farmacologia , Feminino , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Piper nigrum , Piperidinas/síntese química , Piperidinas/química , Piperidinas/isolamento & purificação , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/isolamento & purificação
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