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1.
Hum Mol Genet ; 32(11): 1901-1911, 2023 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-36757138

RESUMO

Spinal muscular atrophy (SMA) is a monogenic disease that clinically manifests as severe muscle weakness owing to neurotransmission defects and motoneuron degeneration. Individuals affected by SMA experience neuromuscular weakness that impacts functional activities of daily living. We have used a mouse model of severe SMA (SMNΔ7) to test whether a calcium channel gating modifier (GV-58), alone or in combination with a potassium channel antagonist (3,4-diaminopyridine; 3,4-DAP), can improve neuromuscular function in this mouse model. Bath application of GV-58 alone or in combination with 3,4-DAP significantly restored neuromuscular transmission to control levels in both a mildly vulnerable forearm muscle and a strongly vulnerable trunk muscle in SMNΔ7 mice at postnatal days 10-12. Similarly, acute subcutaneous administration of GV-58 to postnatal day 10 SMNΔ7 mice, alone or in combination with 3,4-DAP, significantly increased a behavioral measure of muscle strength. These data suggest that GV-58 may be a promising treatment candidate that could address deficits in neuromuscular function and strength and that the addition of 3,4-DAP to GV-58 treatment could aid in restoring function in SMA.


Assuntos
Atividades Cotidianas , Atrofia Muscular Espinal , Humanos , Camundongos , Animais , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Neurônios Motores/fisiologia , Músculo Esquelético , Modelos Animais de Doenças , Transmissão Sináptica , Proteína 1 de Sobrevivência do Neurônio Motor
2.
J Med Ultrasound ; 28(1): 44-47, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368450

RESUMO

This case reports on a patient presenting with abdominal pain of 1-month duration; in whom, ultrasound (US) detected a colonic lipoma with intussusception. Further investigation with computed tomography confirmed this finding, and successful endoscopic removal of the lipoma was performed. This case highlights the importance of careful evaluation of the region of interest during US, knowing the appearance of lipoma on US and other modalities, thus aiding its adequate management.

3.
Bioorg Med Chem ; 27(1): 79-91, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30528127

RESUMO

Over-expression of the Hsp70 molecular chaperone prevents protein aggregation and ameliorates neurodegenerative disease phenotypes in model systems. We identified an Hsp70 activator, MAL1-271, that reduces α-synuclein aggregation in a Parkinson's Disease model. We now report that MAL1-271 directly increases the ATPase activity of a eukaryotic Hsp70. Next, twelve MAL1-271 derivatives were synthesized and examined in a refined α-synuclein aggregation model as well as in an assay that monitors maturation of a disease-causing Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutant, which is also linked to Hsp70 function. Compared to the control, MAL1-271 significantly increased the number of cells lacking α-synuclein inclusions and increased the steady-state levels of the CFTR mutant. We also found that a nitrile-containing MAL1-271 analog exhibited similar effects in both assays. None of the derivatives exhibited cellular toxicity at concentrations up to 100 µm, nor were cellular stress response pathways induced. These data serve as a gateway for the continued development of a new class of Hsp70 agonists with efficacy in these and potentially other disease models.


Assuntos
Adenosina Trifosfatases/metabolismo , Ativadores de Enzimas/farmacologia , Ésteres/farmacologia , Proteínas de Choque Térmico HSP70/agonistas , Multimerização Proteica/efeitos dos fármacos , Pirimidinonas/farmacologia , Linhagem Celular Tumoral , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/química , Ativadores de Enzimas/toxicidade , Ésteres/síntese química , Ésteres/química , Ésteres/toxicidade , Células HEK293 , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Estrutura Molecular , Dobramento de Proteína/efeitos dos fármacos , Pirimidinonas/síntese química , Pirimidinonas/química , Pirimidinonas/toxicidade , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade , alfa-Sinucleína/agonistas , alfa-Sinucleína/metabolismo
4.
Bioorg Med Chem Lett ; 26(15): 3581-5, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27381083

RESUMO

Structure-activity relationship studies of a 1,2,4-triazolo-[3,4-b]thiadiazine scaffold, identified in an HTS campaign for selective STAT3 pathway inhibitors, determined that a pyrazole group and specific aryl substitution on the thiadiazine were necessary for activity. Improvements in potency and metabolic stability were accomplished by the introduction of an α-methyl group on the thiadiazine. Optimized compounds exhibited anti-proliferative activity, reduction of phosphorylated STAT3 levels and effects on STAT3 target genes. These compounds represent a starting point for further drug discovery efforts targeting the STAT3 pathway.


Assuntos
Antineoplásicos/farmacologia , Pirazóis/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Tiadiazinas/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirazóis/química , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Tiadiazinas/síntese química , Tiadiazinas/química , Triazóis/síntese química , Triazóis/química
5.
J Neurosci ; 33(25): 10559-67, 2013 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-23785168

RESUMO

We developed a novel calcium (Ca(2+)) channel agonist that is selective for N- and P/Q-type Ca(2+) channels, which are the Ca(2+) channels that regulate transmitter release at most synapses. We have shown that this new molecule (GV-58) slows the deactivation of channels, resulting in a large increase in presynaptic Ca(2+) entry during activity. GV-58 was developed as a modification of (R)-roscovitine, which was previously shown to be a Ca(2+) channel agonist, in addition to its known cyclin-dependent kinase activity. In comparison with the parent molecule, (R)-roscovitine, GV-58 has a ∼20-fold less potent cyclin-dependent kinase antagonist effect, a ∼3- to 4-fold more potent Ca(2+) channel agonist effect, and ∼4-fold higher efficacy as a Ca(2+) channel agonist. We have further evaluated GV-58 in a passive transfer mouse model of Lambert-Eaton myasthenic syndrome and have shown that weakened Lambert-Eaton myasthenic syndrome-model neuromuscular synapses are significantly strengthened following exposure to GV-58. This new Ca(2+) channel agonist has potential as a lead compound in the development of new therapeutic approaches to a variety of disorders that result in neuromuscular weakness.


Assuntos
Agonistas dos Canais de Cálcio/uso terapêutico , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Purinas/uso terapêutico , Tiofenos/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Adulto , Idoso , Animais , Linhagem Celular , Quinases Ciclina-Dependentes/antagonistas & inibidores , Interpretação Estatística de Dados , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Junção Neuromuscular/efeitos dos fármacos , Neurotransmissores/metabolismo , Técnicas de Patch-Clamp , Fosfotransferases/metabolismo , Roscovitina
6.
J Physiol ; 592(16): 3687-96, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25015919

RESUMO

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder in which a significant fraction of the presynaptic P/Q-type Ca(2+) channels critical to the triggering of neurotransmitter release at the neuromuscular junction (NMJ) are thought to be removed. There is no cure for LEMS, and the current most commonly used symptomatic treatment option is a potassium channel blocker [3,4-diaminopyridine (3,4-DAP)] that does not completely reverse symptoms and can have dose-limiting side-effects. We previously reported the development of a novel Ca(2+) channel agonist, GV-58, as a possible alternative treatment strategy for LEMS. In this study, we tested the hypothesis that the combination of GV-58 and 3,4-DAP will elicit a supra-additive increase in neurotransmitter release at LEMS model NMJs. First, we tested GV-58 in a cell survival assay to assess potential effects on cyclin-dependent kinases (Cdks) and showed that GV-58 did not affect cell survival at the relevant concentrations for Ca(2+) channel effects. Then, we examined the voltage dependence of GV-58 effects on Ca(2+) channels using patch clamp techniques; this showed the effects of GV-58 to be dependent upon Ca(2+) channel opening. Based on this mechanism, we predicted an interaction between 3,4-DAP and GV-58. We tested this hypothesis using a mouse passive transfer model of LEMS. Using intracellular electrophysiological ex vivo recordings, we demonstrated that a combined application of 3,4-DAP plus GV-58 had a supra-additive effect that completely reversed the deficit in neurotransmitter release magnitude at LEMS model NMJs. This reversal contrasts with the less significant improvement observed with either compound alone. Our data indicate that a combination of 3,4-DAP and GV-58 represents a promising treatment option for LEMS and potentially for other disorders of the NMJ.


Assuntos
4-Aminopiridina/análogos & derivados , Agonistas dos Canais de Cálcio/farmacologia , Síndrome Miastênica de Lambert-Eaton/metabolismo , Junção Neuromuscular/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Purinas/farmacologia , Potenciais Sinápticos , Tiofenos/farmacologia , 4-Aminopiridina/farmacologia , Amifampridina , Animais , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Síndrome Miastênica de Lambert-Eaton/fisiopatologia , Camundongos , Junção Neuromuscular/fisiopatologia , Purinas/uso terapêutico , Tiofenos/uso terapêutico
7.
Bioorg Med Chem ; 22(22): 6490-6502, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25440730

RESUMO

Polyomavirus infections are common and relatively benign in the general human population but can become pathogenic in immunosuppressed patients. Because most treatments for polyomavirusassociated diseases nonspecifically target DNA replication, existing treatments for polyomavirus infection possess undesirable side effects. However, all polyomaviruses express Large Tumor Antigen (T Ag), which is unique to this virus family and may serve as a therapeutic target. Previous screening of pyrimidinone­peptoid hybrid compounds identified MAL2-11B and a MAL2-11B tetrazole derivative as inhibitors of viral replication and T Ag ATPase activity (IC50 of ~20-50 µM. To improve upon this scaffold and to develop a structure­activity relationship for this new class of antiviral agents, several iterative series of MAL2-11B derivatives were synthesized. The replacement of a flexible methylene chain linker with a benzyl group or, alternatively, the addition of an ortho-methyl substituent on the biphenyl side chain in MAL2-11B yielded an IC50 of 50 µM, which retained antiviral activity. After combining both structural motifs, a new lead compound was identified that inhibited T Ag ATPase activity with an IC50 of 50 µM. We suggest that the knowledge gained from the structure­activity relationship and a further refinement cycle of the MAL2-11B scaffold will provide a specific, novel therapeutic treatment option for polyomavirus infections and their associated diseases.


Assuntos
Antígenos Virais de Tumores/química , Antivirais/síntese química , Vírus 40 dos Símios/metabolismo , Bibliotecas de Moléculas Pequenas/química , Antígenos Virais de Tumores/metabolismo , Antivirais/farmacologia , Antivirais/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Peptoides/química , Polyomavirus/efeitos dos fármacos , Ligação Proteica , Pirimidinonas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
8.
ACS Med Chem Lett ; 14(7): 977-985, 2023 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-37465292

RESUMO

The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved caspase 3, were observed. Compound (R)-29 (UPCDC-30766) represents the most potent allosteric inhibitor of p97 reported to date.

9.
Tetrahedron Lett ; 50(49): 6810-6813, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20160922

RESUMO

Microwave irradiation facilitated the synthesis of 4-arylthio-3-oxazolin-5-ones from ethyl cyanoformate, thiophenol, and cyclic ketones. Subsequent decarboxylation and in situ [3+2] cycloaddition provided novel 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-c][1,3]diazepine scaffolds after a spontaneous retro-Mannich domino reaction.

10.
J Radiol Case Rep ; 13(10): 1-10, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32184921

RESUMO

We present a case of a 65 year old female with newly diagnosed primary peritoneal serous carcinoma who was found to have indeterminate segmental microcalcifications in the right upper outer quadrant with a mildly enlarged right axillary node on mammogram. There was no associated breast mass on ultrasound. Core biopsy of the right axillary lymph node and right upper outer quadrant breast microcalcifications confirmed the presence of breast metastases at both sites from primary peritoneal serous carcinoma. This case highlights the importance of histopathological correlation of any breast and axillary abnormalities in patient with primary extramammary malignancy. Imaging features of metastatic lesions to the breast are also reviewed.


Assuntos
Doenças Mamárias/diagnóstico por imagem , Neoplasias da Mama/secundário , Calcinose/diagnóstico por imagem , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/secundário , Neoplasias Peritoneais/patologia , Idoso , Feminino , Humanos , Linfonodos/diagnóstico por imagem , Metástase Linfática , Mamografia
11.
Org Lett ; 10(2): 341-4, 2008 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-18095698

RESUMO

Asymmetric hydrogenation of unsaturated urea esters with the BIPI Ligands has been examined. Optimization of the P-N ligand structure has led to the development of chiral rhodium catalysts capable of producing the targets with >99% ee. The critical phosphine borane SNAr reaction needed for ligand synthesis has been optimized to give the adducts in high yield at ambient temperature with no racemization. An extremely concise, economical, and scalable sequence to these important new ligands for catalysis of asymmetric hydrogenation has been developed.


Assuntos
Fosfinas/química , Ródio/química , Ureia/análogos & derivados , Ureia/química , Catálise , Ésteres , Hidrogenação , Ligantes , Estrutura Molecular , Estereoisomerismo
12.
Ann N Y Acad Sci ; 1412(1): 73-81, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29125190

RESUMO

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage-gated calcium channels that provide the calcium ion flux that triggers acetylcholine release at the neuromuscular junction. To study the pathophysiology of LEMS and test candidate therapeutic strategies, a passive-transfer animal model has been developed in mice, which can be created by daily intraperitoneal injections of LEMS patient serum or IgG into mice for 2-4 weeks. Results from studies of the mouse neuromuscular junction have revealed that each synapse has hundreds of transmitter release sites but that the probability for release at each one is likely to be low. LEMS further reduces this low probability such that transmission is no longer effective at triggering a muscle contraction. The LEMS-mediated attack reduces the number of presynaptic calcium channels, disorganizes transmitter release sites, and results in the homeostatic upregulation of other calcium channel types. Symptomatic treatment is focused on increasing the probability of release from dysfunctional release sites. Current treatment uses the potassium channel blocker 3,4-diaminopyridine (DAP) to broaden the presynaptic action potential, providing more time for calcium channels to open. Current research is focused on testing new calcium channel gating modifiers that work synergistically with DAP.


Assuntos
Síndrome Miastênica de Lambert-Eaton/etiologia , Animais , Autoantígenos , Carcinoma de Células Pequenas/etiologia , Modelos Animais de Doenças , Humanos , Imunização Passiva , Síndrome Miastênica de Lambert-Eaton/patologia , Síndrome Miastênica de Lambert-Eaton/terapia , Neoplasias Pulmonares/etiologia , Camundongos , Junção Neuromuscular/patologia , Junção Neuromuscular/fisiopatologia , Neurotransmissores/fisiologia
13.
Neuropharmacology ; 131: 176-189, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29246857

RESUMO

Voltage-gated calcium channels (VGCCs) are critical regulators of many cellular functions, including the activity-dependent release of chemical neurotransmitter from nerve terminals. At nerve terminals, the Cav2 family of VGCCs are closely positioned with neurotransmitter-containing synaptic vesicles. The relationship between calcium ions and transmitter release is such that even subtle changes in calcium flux through VGCCs have a strong influence on the magnitude of transmitter released. Therefore, modulators of the calcium influx at nerve terminals have the potential to strongly affect transmitter release at synapses. We have previously developed novel Cav2-selective VGCC gating modifiers (notably GV-58) that slow the deactivation of VGCC current, increasing total calcium ion flux. Here, we describe ten new gating modifiers based on the GV-58 structure that extend our understanding of the structure-activity relationship for this class of molecules and extend the range of modulation of channel activities. In particular, we show that one of these new compounds (MF-06) was more efficacious than GV-58, another (KK-75) acts more quickly on VGCCs than GV-58, and a third (KK-20) has a mix of increased speed and efficacy. A subset of these new VGCC agonist gating modifiers can increase transmitter release during action potentials at neuromuscular synapses, and as such, show potential as therapeutics for diseases with a presynaptic deficit that results in neuromuscular weakness. Further, several of these new compounds can be useful tool compounds for the study of VGCC gating and function.


Assuntos
Agonistas dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Ativação do Canal Iônico/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Biofísica , Agonistas dos Canais de Cálcio/química , Canais de Cálcio Tipo N/genética , Linhagem Celular , Relação Dose-Resposta a Droga , Estimulação Elétrica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/genética , Neuroblastoma/patologia , Neurotransmissores/metabolismo , Técnicas de Patch-Clamp , Purinas/química , Purinas/farmacologia , Transmissão Sináptica/genética , Tiofenos/química , Tiofenos/farmacologia , Fatores de Tempo , Transfecção
14.
In Vivo ; 31(1): 39-43, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-28064218

RESUMO

BACKGROUND/AIM: Mitochondrial-targeted gramicidin S (GS)-nitroxide, JP4-039, has been demonstrated to be a potent radiation mitigator, and safe over a wide dose range. In addition, JP4-039 has organ-specific effectiveness when locally applied. MATERIALS AND METHODS: We tested the effect of another GS-nitroxide, XJB-5-131, which has more effective mitochondrial localization, and compared these results to those for radiation mitigation against the hematopoietic syndrome, and two analogs of JP4-039, which have the same mitochondrial localization signal, but different chemical payloads: JRS527.084 contains a second nitroxide per molecule, and TK649.030 contains an ester group attached to the nitroxide. RESULTS: The results demonstrate the superiority of JP4-039 as a systemic radiation mitigator. CONCLUSION: Structure-activity relationships and bioassays demonstrate that JP4-039 is an optimized small-molecule radiation mitigator.


Assuntos
Óxidos de Nitrogênio/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Irradiação Corporal Total/efeitos adversos , Animais , Relação Dose-Resposta à Radiação , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Lesões Experimentais por Radiação/etiologia , Protetores contra Radiação/administração & dosagem , Relação Estrutura-Atividade
15.
ACS Med Chem Lett ; 7(2): 182-7, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26985295

RESUMO

A high-throughput screen to discover inhibitors of p97 ATPase activity identified an indole amide that bound to an allosteric site of the protein. Medicinal chemistry optimization led to improvements in potency and solubility. Indole amide 3 represents a novel uncompetitive inhibitor with excellent physical and pharmaceutical properties that can be used as a starting point for drug discovery efforts.

17.
ACS Med Chem Lett ; 6(12): 1225-30, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26713109

RESUMO

Exploratory SAR studies of a new phenyl indole chemotype for p97 inhibition revealed C-5 indole substituent effects in the ADPGlo assay that did not fully correlate with either electronic or steric factors. A focused series of methoxy-, trifluoromethoxy-, methyl-, trifluoromethyl-, pentafluorosulfanyl-, and nitro-analogues was found to exhibit IC50s from low nanomolar to double-digit micromolar. Surprisingly, we found that the trifluoromethoxy-analogue was biochemically a better match of the trifluoromethyl-substituted lead structure than a pentafluorosulfanyl-analogue. Moreover, in spite of their almost equivalent strongly electron-depleting effect on the indole core, pentafluorosulfanyl- and nitro-derivatives were found to exhibit a 430-fold difference in p97 inhibitory activities. Conversely, the electronically divergent C-5 methyl- and nitro-analogues both showed low nanomolar activities.

18.
Int J Antimicrob Agents ; 43(3): 262-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24359836

RESUMO

Imidazolium salts are best known for their applications in organic synthesis as room-temperature ionic liquids, or as precursors of stable carbenes, but they also show important biological properties such as anti-oxidative effects, induction of mitochondrial membrane permeabilisation and inhibition of the infection cycle of Plasmodium falciparum. For these reasons, and since chemotherapy for Chagas disease is inefficient, the aim of this study was to test the use of imidazolium compounds against the kinetoplastid haemoflagellate aetiological agent for this disease, namely Trypanosoma cruzi. The results show that five of the tested compounds are more effective than the reference drug benznidazole against the epimastigote and trypomastigote forms of T. cruzi. Moreover, intracellular amastigotes were also affected by the compounds, which showed lower toxicity in host cells. Transmission electron microscopy analysis demonstrated that the tested agents induced alterations of the kinetoplast and particularly of the mitochondria, leading to extraordinary swelling of the organelle. These results further demonstrate that the test agents with the best profile are those bearing symmetrical bulky substituents at N(1) and N(3), displaying promising activity against all forms of T. cruzi, interesting selectivity indexes and exceptional activity at low doses. Accordingly, these agents represent promising candidates for the treatment of Chagas disease.


Assuntos
Antiprotozoários/farmacologia , Imidazóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Imidazóis/química , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Nitroimidazóis/química , Nitroimidazóis/farmacologia , Relação Estrutura-Atividade , Trypanosoma cruzi/ultraestrutura
19.
Ann N Y Acad Sci ; 1275: 85-91, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23278582

RESUMO

Lambert-Eaton myasthenic syndrome (LEMS) causes neuromuscular weakness as a result of an autoimmune attack on the calcium channels that normally regulate chemical transmitter release at the neuromuscular junction. Currently there are limited treatment options for patients with this and other forms of neuromuscular weakness. A novel, first-in-class calcium channel agonist that is selective for the types of voltage-gated calcium channels that regulate transmitter release at neuromuscular synapses has recently been developed. This compound (GV-58) slows deactivation (closing) of the channel, resulting in a large increase in total calcium entry during motor nerve action potential activity. This new calcium channel agonist is currently being evaluated for the treatment of neuromuscular weakness. Potential applications include development as single therapeutics, or for combination treatments.


Assuntos
Agonistas dos Canais de Cálcio/uso terapêutico , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Doenças Neuromusculares/tratamento farmacológico , Purinas/uso terapêutico , Tiofenos/uso terapêutico , Humanos , Roscovitina
20.
ACS Med Chem Lett ; 3(12): 985-90, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-24936234

RESUMO

The acute effect of the potent cyclin-dependent kinase (cdk) inhibitor (R)-roscovitine on Ca(2+) channels inspired the development of structural analogues as a potential treatment for motor nerve terminal dysfunction. On the basis of a versatile chlorinated purine scaffold, we have synthesized ca. 20 derivatives and characterized their N-type Ca(2+) channel agonist action. Agents that showed strong agonist effects were also characterized in a kinase panel for their off-target effects. Among several novel compounds with diminished cdk activity, we identified a new lead structure with a 4-fold improved N-type Ca(2+) channel agonist effect and a 22-fold decreased cdk2 activity as compared to (R)-roscovitine. This compound was selective for agonist activity on N- and P/Q-type over L-type calcium channels.

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