RESUMO
Neuromuscular blocking agents (NMBAs) are routinely used during anesthesia to relax skeletal muscle. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels; NMBAs can induce muscle paralysis by preventing the neurotransmitter acetylcholine (ACh) from binding to nAChRs situated on the postsynaptic membranes. Despite widespread efforts, it is still a great challenge to find new NMBAs since the introduction of cisatracurium in 1995. In this work, an effective ensemble-based virtual screening method, including molecular property filters, 3D pharmacophore model, and molecular docking, was applied to discover potential NMBAs from the ZINC15 database. The results showed that screened hit compounds had better docking scores than the reference compound d-tubocurarine. In order to further investigate the binding modes between the hit compounds and nAChRs at simulated physiological conditions, the molecular dynamics simulation was performed. Deep analysis of the simulation results revealed that ZINC257459695 can stably bind to nAChRs' active sites and interact with the key residue Asp165. The binding free energies were also calculated for the obtained hits using the MM/GBSA method. In silico ADMET calculations were performed to assess the pharmacokinetic properties of hit compounds in the human body. Overall, the identified ZINC257459695 may be a promising lead compound for developing new NMBAs as an adjunct to general anesthesia, necessitating further investigations.
Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Bloqueadores Neuromusculares , Receptores Nicotínicos , Bloqueadores Neuromusculares/química , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/química , Humanos , Descoberta de Drogas/métodos , Ligação Proteica , Sítios de Ligação , LigantesRESUMO
Neuromuscular blocking agents (NMBAs) are widely used in anesthesia for intubation and surgical muscle relaxation. Novel atracurium and mivacurium derivatives were developed, with compounds 18c, 18d, and 29a showing mivacurium-like relaxation at 27.27 nmol/kg, and 15b, 15c, 15e, and 15h having a shorter duration at 272.7 nmol/kg. The structure-activity and configuration-activity relationships of these derivatives and 29a's binding to nicotinic acetylcholine receptors were analyzed through molecular docking. Rabbit trials showed 29a has a shorter duration compared to mivacurium. This suggests that linker properties, ammonium group substituents, and configuration are crucial for NMBA activity and duration, with compound 29a emerging as a potential ultra-short-acting NMBA.
Assuntos
Desenho de Fármacos , Isoquinolinas , Bloqueadores Neuromusculares , Bloqueadores Neuromusculares/farmacologia , Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/química , Relação Estrutura-Atividade , Animais , Isoquinolinas/química , Isoquinolinas/farmacologia , Isoquinolinas/síntese química , Coelhos , Receptores Nicotínicos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Dose-Resposta a Droga , Mivacúrio , Atracúrio/análogos & derivados , Atracúrio/farmacologia , Atracúrio/síntese química , Atracúrio/químicaRESUMO
We report on the synthesis of bivalent water-soluble calix[4]arene and calix[5]arene hosts, Super-sCx4 and Super-sCx5 as new broad-spectrum supramolecular binders of neuromuscular blocking agents (NMBAs). Synthesis was achieved using the target bisquaternary amine NMBAs as a template to link two highly anionic p-sulfonatocalixarene building blocks in aqueous solution. Bivalent anionic hosts Super-sCx4 and Super-sCx5 bind by engaging both quaternary amines present on a variety of NMBAs. We report low µM binding to structurally diverse alkyl, steroidal, curarine and benzylisoquinoline NMBAs with high selectivity over the neurotransmitter acetylcholine and a variety of other hydrophobic amines.
Assuntos
Calixarenos/síntese química , Bloqueadores Neuromusculares/síntese química , Aminas/química , Calixarenos/química , Estrutura Molecular , Bloqueadores Neuromusculares/químicaRESUMO
Vecuronium bromide (Piperidinium, 1-[(2ß,3α,5α,16ß,17ß)-3,17-bis(acetyloxy)-2-(1-piperidinyl)androstan-16-yl]-1-methyl-, bromide; Norcuron®) has been extensively used in anesthesiology practice as neuromuscular blocking agent since its launch on the market in 1982. However, a detailed crystallographic and NMR analysis of its advanced synthetic intermediates is still lacking. Hence, with the aim of filling this literature gap, vecuronium bromide was prepared starting from the commercially available 3ß-hydroxy-5α-androstan-17-one (epiandrosterone), implementing some modifications to a traditional synthetic procedure. A careful NMR study allowed the complete assignment of the 1H, 13C, and 15N NMR signals of vecuronium bromide and its synthetic intermediates. The structural and stereochemical characterization of 2ß,16ß-bispiperidino-5α-androstane-3α,17ß-diol, the first advanced synthetic intermediate carrying all the stereocenters in the final configuration, was described by means of single-crystal X-ray diffraction and Hirshfeld surface analysis, allowing a detailed conformational investigation.
Assuntos
Bloqueadores Neuromusculares/química , Brometo de Vecurônio/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Brometo de Vecurônio/análogos & derivadosRESUMO
Thiazolo- and thiadiazolo-[3,2-a][1,3]diazepines and their patented derivatives, tested with diverse CNS pharmacological activities, constitute an important class of compounds for new drug development. Therefore, research efforts were continued to design, synthesize, and evaluate compounds for their ultra-short, short-acting hypnotic, anticonvulsant, and neuromuscular blocking activities. The present review provides a summary of the work accomplished by these heterocycles and their biological evaluation.
Assuntos
Anticonvulsivantes/farmacologia , Azepinas/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Bloqueadores Neuromusculares/farmacologia , Receptores de GABA-A/metabolismo , Tiazóis/farmacologia , Animais , Anticonvulsivantes/química , Azepinas/química , Agonistas de Receptores de GABA-A/química , Humanos , Modelos Moleculares , Estrutura Molecular , Bloqueadores Neuromusculares/química , Tiazóis/químicaRESUMO
Between 1938 and 1951 erythroidine derivatives were seriously considered as alternatives to curare for the provision of muscle relaxation. This has been overlooked in the published history of anaesthesia. The first publication on the paralysing effect of an extract of Erythrina americana was in 1877, but this was in a Mexican journal, which was not widely read. Sixty years later erythroidine was isolated, and in 1938 it was first used clinically to treat spastic dystonia, preceding the use of Intocostrin for this purpose. By 1943 dihydro-ß-erythroidine was prepared in crystalline form, which was equipotent with curarine and of acceptable duration; it was used in clinical anaesthesia in 1946. In the 1940s curare was presented in solutions with potency stated in units, determined by bioassay, which was a disadvantage compared with the straightforward mg of dihydro-ß-erythroidine. However, by the early 1950s, improvement in the pharmaceutical presentation of d-tubocurarine and new neuromuscular blockers, displaced the erythroidines.
Assuntos
Anestesia/história , Curare/história , Di-Hidro-beta-Eritroidina/história , Bloqueadores Neuromusculares/história , Anestesia/métodos , Di-Hidro-beta-Eritroidina/química , Di-Hidro-beta-Eritroidina/farmacologia , História do Século XX , Humanos , Relaxamento Muscular/efeitos dos fármacos , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/farmacologiaRESUMO
We synthesized a family of neuromuscular blocking agents (NMB) based on decamethonium, but containing a carborane cluster in the methylene chain between the two quaternary ammonium groups. The carborane cluster isomers o-NMB, m-NMB, and p-NMB were tested in animals for neuromuscular block and compared with agents used clinically: rocuronium and decamethonium. All three isomers caused reversible muscle weakness in mice as determined by grip strength and inverted screen tests, with a potency rank of p-NMB > rocuronium > decamethonium > m-NMB > o-NMB. The mechanism of action of the compounds was determined by using the inâ vitro rat phrenic nerve hemi-diaphragm preparation and electrophysiologic measurements in cells. Neostigmine reversed hemi-diaphragm weakness caused by the three isomers and rocuronium, but not succinylcholine. In electrophysiologic recordings of currents through acetylcholine receptor channels, the carborane compounds did not activate channel activity but did inhibit channel activation by acetylcholine. These results demonstrate that the carborane neuromuscular blocking agents are non-depolarizers in contrast to the depolarizing action of the parent compound.
Assuntos
Boranos/farmacologia , Força Muscular/efeitos dos fármacos , Bloqueadores Neuromusculares/farmacologia , Animais , Boranos/síntese química , Boranos/química , Relação Dose-Resposta a Droga , Masculino , Camundongos , Estrutura Molecular , Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/química , Ratos , Ratos Sprague-Dawley , EstereoisomerismoRESUMO
Anuran toxins released from the skin glands are involved in defence against predators and microorganisms. Secretion from parotoid macroglands of bufonid toads is a rich source of bioactive compounds with the cytotoxic, cardiotoxic and hemolytic activity. Bufadienolides are considered the most toxic components of the toad poison, whereas the protein properties are largely unknown. In the present work, we analysed the cardio-, myo-, and neurotropic activity of extract and the selected proteins from Bufo bufo parotoids in in vitro physiological bioassays carried out on two standard model organisms: beetles and frogs. Our results demonstrate a strong cardioactivity of B. bufo gland extract. The toad poison stimulates (by 16%) the contractility of the insect heart and displays the cardioinhibitory effect on the frog heartbeat frequency (a 27% decrease), coupled with an irreversible cardiac arrest. The gland extract also exhibits significant myotropic properties (a 10% decrease in the muscle contraction force), whereas its neuroactivity remains low (a 4% decrease in the nerve conduction velocity). Among identified peptides present in the B. bufo parotoid extract are serine proteases, muscle creatine kinase, phospholipid hydroperoxide glutathione peroxidase, cytotoxic T-lymphocyte protein, etc. Some proteins contribute to the cardioinhibitory effect. Certain compounds display the paralytic (myo- and neurotropic) properties. As the toad gland extract exhibits a strong cardiotoxic activity, we conclude that the poison is a potent agent capable of slaying a predator. Our results also provide the guides for the use of toad poison-peptides in therapeutics and new drug development.
Assuntos
Proteínas de Anfíbios/toxicidade , Venenos de Anfíbios/toxicidade , Bufo bufo/fisiologia , Cardiotoxinas/toxicidade , Bloqueadores Neuromusculares/toxicidade , Neurotoxinas/toxicidade , Pele/metabolismo , Proteínas de Anfíbios/química , Proteínas de Anfíbios/isolamento & purificação , Proteínas de Anfíbios/metabolismo , Venenos de Anfíbios/química , Venenos de Anfíbios/isolamento & purificação , Venenos de Anfíbios/metabolismo , Animais , Bufo bufo/crescimento & desenvolvimento , Cardiotoxinas/química , Cardiotoxinas/isolamento & purificação , Cardiotoxinas/metabolismo , Feminino , Jardins , Coração/efeitos dos fármacos , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Membro Posterior , Técnicas In Vitro , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Condução Nervosa/efeitos dos fármacos , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/isolamento & purificação , Bloqueadores Neuromusculares/metabolismo , Neurotoxinas/química , Neurotoxinas/isolamento & purificação , Neurotoxinas/metabolismo , Parques Recreativos , Polônia , Proteômica/métodos , Ranidae , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologia , TenebrioRESUMO
While some US populations of the Mohave rattlesnake (Crotalus scutulatus scutulatus) are infamous for being potently neurotoxic, the Mexican subspecies C. s. salvini (Huamantlan rattlesnake) has been largely unstudied beyond crude lethality testing upon mice. In this study we show that at least some populations of this snake are as potently neurotoxic as its northern cousin. Testing of the Mexican antivenom Antivipmyn showed a complete lack of neutralisation for the neurotoxic effects of C. s. salvini venom, while the neurotoxic effects of the US subspecies C. s. scutulatus were time-delayed but ultimately not eliminated. These results document unrecognised potent neurological effects of a Mexican snake and highlight the medical importance of this subspecies, a finding augmented by the ineffectiveness of the Antivipmyn antivenom. These results also influence our understanding of the venom evolution of Crotalus scutulatus, suggesting that neurotoxicity is the ancestral feature of this species, with the US populations which lack neurotoxicity being derived states.
Assuntos
Venenos de Crotalídeos/metabolismo , Crotalus/fisiologia , Evolução Molecular , Músculo Esquelético/efeitos dos fármacos , Bloqueadores Neuromusculares/metabolismo , Neurotoxinas/metabolismo , Proteínas de Répteis/metabolismo , Animais , Antivenenos/farmacologia , Arizona , Galinhas , Venenos de Crotalídeos/antagonistas & inibidores , Venenos de Crotalídeos/química , Venenos de Crotalídeos/toxicidade , Crotalus/crescimento & desenvolvimento , Clima Desértico , Feminino , Técnicas In Vitro , Dose Letal Mediana , Masculino , México , Camundongos Endogâmicos BALB C , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/inervação , Bloqueadores Neuromusculares/antagonistas & inibidores , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/toxicidade , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/química , Neurotoxinas/toxicidade , Fosfolipases A2/química , Fosfolipases A2/metabolismo , Fosfolipases A2/toxicidade , Proteômica/métodos , Proteínas de Répteis/antagonistas & inibidores , Proteínas de Répteis/química , Proteínas de Répteis/toxicidade , Especificidade da Espécie , Especificidade por Substrato , TexasRESUMO
Steroid and its derivatives have been proved to have important and diverse biological functions, which present the wide spectrum of biological activities such as antitumor, antiviral, antibacterial, antimicrobial, antifungal, antioxidant, insecticidal, aromatase inhibitors, 5α-reductase inhibitors and neuromuscular blocking agents etc. Versatile features of steroid-derived compounds have emerged, so the aim of the present paper is to review the recent advances of steroid-based derivatives mainly focused on their structures and biological applications, which can be employed for further development to discover potential drug candidates.
Assuntos
Produtos Biológicos/farmacologia , Esteroides/farmacologia , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Humanos , Inseticidas/síntese química , Inseticidas/química , Inseticidas/farmacologia , Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/farmacologia , Esteroides/síntese química , Esteroides/químicaRESUMO
The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2-a][1,3]diazepine analogues as new class of neuromuscular blocking agents are described. The new compounds act via competitive mechanism with ACh which could be reversed by the anticholinesterase - Physostigmine. Compounds GS-53 (30) and AAH1 (33) induced dose-dependent neuromuscular blockade with onset time of 3 and 10 min, ED50 0.15 and 0.36 mmol/kg i.p., respectively, in rats. Compound 30 proved to be as twice as potent as 33 with rapid onset and shorter duration (P < 0.05). Docking profile of 30 and 33 closely resembles HIE-124 (3), in α7ß2 nAChR receptor. Molecular modeling analysis indicated that hydrogen bonding to Thr120 and Thr124 beside hydrophobic interactions play effective role incorporating the active ligands to nAChR. The obtained model could be useful for further development of new skeletal muscle relaxants.
Assuntos
Desenho de Fármacos , Simulação de Acoplamento Molecular , Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Técnicas de Química Sintética , Galinhas , Masculino , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/metabolismo , Conformação Proteica , Ratos , Tiadiazóis/química , Tiadiazóis/metabolismoRESUMO
An acyclic cucurbit[n]uril (CB[n]) based molecular container (2, a.k.a. Calabadion 2) binds to both amino-steroidal and benzylisoquinolinium type neuromuscular blocking agents (NMBAs) in vitro, and reverses the effect of these drugs in vivo displaying faster recovery times than placebo and the γ-cyclodextrin (CD) based and clinically used reversal agent Sugammadex. In this study we have assessed the potential for other drugs commonly used during and after surgery (e.g. antibiotics, antihistamines, and antiarrhythmics) to interfere with the ability of 2 to bind NMBAs rocuronium and cisatracurium in vitro. We measured the binding affinities (Ka, M(-1)) of twenty seven commonly used drugs towards 2 and simulated the equilibrium between 2, NMBA, and drug based on their standard clinical dosages to calculate the equilibrium concentration of 2·NMBA in the presence of the various drugs. We found that none of the 27 drugs studied possess the combination of a high enough binding affinity with 2 and a high enough standard dosage to be able to promote the competitive dissociation (a.k.a. displacement interactions) of the 2·NMBA complex with the formation of the 2·drug complex. Finally, we used the simulations to explore how the potential for displacement interactions is affected by a number of factors including the Ka of the 2·NMBA complex, the Ka of the AChR·NMBA complex, the Ka of the 2·drug complex, and the dosage of the drug.
Assuntos
Compostos Macrocíclicos/farmacologia , Bloqueadores Neuromusculares/farmacologia , Receptores Colinérgicos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Compostos Macrocíclicos/química , Conformação Molecular , Bloqueadores Neuromusculares/química , Receptores Colinérgicos/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
PURPOSE: The physical compatibility of cisatracurium with selected drugs during simulated Y-site administration was studied. METHODS: Study drugs were selected based on the lack of physical compatibility data with cisatracurium and their use in intensive care units. Test admixtures were prepared by mixing 2.5-mL samples of varying concentrations of calcium gluconate, diltiazem, esomeprazole, regular insulin, nicardipine, pantoprazole, and vasopressin with either 2.5 mL of normal saline 0.9% (control) or 2.5 mL of cisatracurium (experimental) to simulate a 1:1 Y-site ratio. Drug infusions were prepared at the maximum concentrations used clinically. Physical compatibility of the admixtures was determined by visual and turbidimetric assessments performed in triplicate immediately after mixing and at 15, 30, and 60 minutes. Visual incompatibility was defined as a change in color, the formation of haze or precipitate, the presence of particles, or the formation of gas in the experimental groups compared with the controls. Disturbances invisible to the naked eye were determined by assessing changes in turbidity of experimental admixtures compared with the controls. RESULTS: None of the admixtures exhibited visual changes when mixed with cisatracurium. Six of the seven admixtures exhibited turbidimetric compatibility with cisatracurium. Pantoprazole admixtures demonstrated a significant difference in turbidimetric assessment between the control and experimental groups when mixed with cisatracurium (p < 0.001). CONCLUSION: Calcium gluconate, diltiazem hydrochloride, esomeprazole, regular insulin, nicardipine hydrochloride, and vasopressin demonstrated physical compatibility with cisatracurium over 60 minutes during simulated Y-site administration. Cisatracurium and pantoprazole should not be coadministered due to a significant difference in turbidity between control and experimental samples.
Assuntos
Atracúrio/análogos & derivados , Química Farmacêutica , Bloqueadores Neuromusculares/química , Atracúrio/administração & dosagem , Atracúrio/química , Composição de Medicamentos , Incompatibilidade de Medicamentos , Humanos , Infusões Intravenosas , Unidades de Terapia Intensiva , Nefelometria e Turbidimetria , Bloqueadores Neuromusculares/administração & dosagem , Fatores de TempoRESUMO
Neuromuscular blocking agents (NMBAs) are widely used in surgery to achieve skeleton muscles relaxation under light anesthesia status. In this work, we synthesized a series of 3,16-bisquaternary ammonium steroidal NMBAs. Among them, three compounds exhibited higher in vitro activities than the commenced drug rocuronium. In addition, structure-activity relationship was unveiled. We found that the intact acetylcholine-like moiety in D-ring was not necessary for maintaining activity but both the acetyl group and the quaternary nitrogen were very essential.
Assuntos
Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/farmacologia , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/farmacologia , Esteroides/química , Animais , Técnicas de Química Sintética , Masculino , Camundongos , Bloqueadores Neuromusculares/química , Compostos de Amônio Quaternário/química , Relação Estrutura-AtividadeRESUMO
Up to now, there have been a few reports on the toxic components purified from black widow spider (Latrodectus tredecimguttatus) eggs. In the present study, a novel neurotoxic protein was purified from the eggs by gel filtration combined with ion-exchange chromatography. Its molecular weight was 23.752 kDa determined by electrospray mass spectrometry. The protein could block the neuromuscular transmission in mouse-isolated phrenic nerve-hemidiaphragm preparations completely in a reversible manner and activate tetrodotoxin-sensitive sodium current in rat dorsal root ganglion cells. The N-terminal sequence of the protein was identified by the Edman degradation to be N-S-I-A-D-D-R-Y-R-W-P-G-Y-P-G-A-G-L-I-P-Y-I-I-D-S-. When the sequence was used to search against protein database with a sequence query in Mascot engine there was no matched sequence or protein whereas the Basic Local Alignment Search Tool (BLAST) analysis indicated that no significant similarity was found. These results demonstrated that the protein (named Latroeggtoxin-I) is a novel neurotoxic protein purified from the eggs of black widow spiders.
Assuntos
Proteínas de Artrópodes , Viúva Negra/química , Bloqueadores Neuromusculares , Neurotoxinas , Óvulo/química , Transmissão Sináptica/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/isolamento & purificação , Proteínas de Artrópodes/toxicidade , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Bloqueadores Neuromusculares/efeitos adversos , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/isolamento & purificação , Bloqueadores Neuromusculares/farmacologia , Neurotoxinas/química , Neurotoxinas/isolamento & purificação , Neurotoxinas/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
A series of steroidal 3,16-bis-quaternary ammonium salts were synthesized and screened on mouse hemi-diaphragm to explore new steroidal neuromuscular blocking agents. There were two compounds, 3ß-piperidino derivate 8d (IC(50) = 3.49 µM) and 3ß-N-methylbenzylamino derivate 8g (IC(50) = 4.54 µM), showing activity close to rocuronium (IC(50) = 2.50 µM). The preliminary structure-activity relationship was deduced from the bioactivity results with the aid of the calculated N-N distance and log P. Meanwhile, the interactions between the ligand and binding pocket were revealed by docking 8d to the ligand binding domain of the mouse muscle nicotinic acetylcholine receptor (nAChR). This nAChR was modeled using Molecular Operating Environment (MOE) package indirectly from mollusca acetylcholine binding protein with mouse neuron α7 nAChR as intermediary template.
Assuntos
Sondas Moleculares/farmacologia , Morfolinas/farmacologia , Bloqueadores Neuromusculares/farmacologia , Compostos de Amônio Quaternário/farmacologia , Receptores Nicotínicos/metabolismo , Esteroides/farmacologia , Animais , Diafragma/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ligantes , Masculino , Camundongos , Sondas Moleculares/síntese química , Sondas Moleculares/química , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/química , Músculo Esquelético/efeitos dos fármacos , Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/química , Neurônios/efeitos dos fármacos , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Esteroides/síntese química , Esteroides/química , Relação Estrutura-AtividadeRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia ludoviciana spp. mexicana (Willd. Ex.) Spring D.D. Keck (Asteraceae), known as "estafiate" is employed for the treatment of diarrhea, dysentery, parasites, abdominal pain, vomiting, stomach ache, and also as antispasmodic agent. The aim of the present study was to evaluate the relaxant effect of hexanic (HEAl), dichloromethanic (DEAl) and methanolic (MEAl) extracts on isolated trachea, ileum and aorta rat rings, and to establish the tracheo-relaxant mode of action of DEAl. MATERIALS AND METHODS: All extracts were investigated based on their capacity of to inhibit the rat ileum spontaneous contraction, to relax contraction induced by noradrenaline (0.1 µM) on endothelium-intact and endothelium-denuded thoracic aorta rat rings, and also to inhibit contraction provoked by carbachol (1 µM) on rat trachea. RESULTS: Organic extracts had no spasmolytic action on ileum strips compared to positive control (papaverine, p<0.05). On the other hand, all extracts induced a significant concentration- and partial endothelium-dependent vasorelaxant activity. Extracts also showed significant relaxant effect on pre-contracted tracheal tissue in a concentration-dependent manner. In last two experiments, DEAl was the most potent and efficient extract; however, it was less potent than papaverine and theophylline, used as positive controls (p<0.05). In tracheal preparation, DEAl shifted to the right, in a parallel manner, the concentration-response curves induced by carbachol (p<0.05). Also, DEAl induced a significant relaxant effect on the contraction produced by potassium chloride (KCl, 80 mM). Pre-incubation with 1-H-[1,2,4]-oxadiazolo-[4,3a]-quinoxalin-1-one (ODQ, 10 µM), indomethacin (10 µM), N(ω)-nitro-L-arginine methyl ester (L-NAME, 10 µM), glibenclamide (10 µM) and 2-aminopyridine (2-AP, 100 µM) did not modify the DEAl-relaxant curves. CONCLUSIONS: Functional experiments suggest that the most active extract, DEAl, induced its relaxant effect by possible muscarinic receptors antagonism and calcium channel blockade in tracheal rings. On the other hand, significant vasorelaxant activity showed by DEAl is partially endothelium-dependent. Finally, spasmolytic activity induced by the extracts in the rat ileum was not significant, which suggests that the antidiarrheic effect of the plant is related to antimicrobial and antiparasitic properties previously described.
Assuntos
Artemisia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Bloqueadores Neuromusculares/farmacologia , Parassimpatolíticos/farmacologia , Preparações de Plantas/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Íleo/efeitos dos fármacos , Masculino , Antagonistas Muscarínicos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Bloqueadores Neuromusculares/química , Parassimpatolíticos/química , Componentes Aéreos da Planta , Preparações de Plantas/química , Plantas Medicinais , Ratos , Ratos Wistar , Solventes/química , Traqueia/efeitos dos fármacosAssuntos
gama-Ciclodextrinas/química , gama-Ciclodextrinas/farmacologia , Anafilaxia/induzido quimicamente , Anafilaxia/imunologia , Anestesia/efeitos adversos , Interações Medicamentosas , Epitopos/imunologia , Humanos , Bloqueadores Neuromusculares/efeitos adversos , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/farmacologia , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Sugammadex , gama-Ciclodextrinas/efeitos adversosRESUMO
Among all drugs used for general anesthesia, neuromuscular blocking agents (NMBAs) seem to play a predominant role in the incidence of severe adverse reactions. The overall incidence of perioperative anaphylaxis is estimated at 1 in 10,000-20,000 anesthetic procedures, whereas it is estimated at 1 in 6,500 administrations of NMBAs. After anaphylaxis, allergologic assessment is essential to identify the offending agent and to prevent recurrences. The estimated sensitivity of skin tests for muscle relaxants is approximately 94% to 97%. Prick testing is advised for the diagnosis of the NMBAs responsible for an anaphylactic reaction, and intradermal testing is preferred when investing cross-reaction. The choice of the safest possible anesthetic agents should be based on the result of a rigorously performed allergologic assessment.
Assuntos
Anafilaxia/induzido quimicamente , Anestesia Geral , Bloqueadores Neuromusculares/efeitos adversos , Período Perioperatório , Anafilaxia/diagnóstico , Anafilaxia/epidemiologia , Histamina , Liberação de Histamina , Humanos , Bloqueadores Neuromusculares/química , Teste de Radioalergoadsorção , Fatores de Risco , Prevenção Secundária , Índice de Gravidade de Doença , Testes Cutâneos , TriptasesRESUMO
Synthesis of eighteen new quaternary ammonium salts of 16E-arylidene androstene derivatives as skeletal muscle relaxants is reported in the present study. The effects of possibly extended interonium distances on muscle relaxant activity are discussed. All the quaternary ammonium steroids produced reduction in the twitch responses, when screened for in vitro neuromuscular blocking activity using isolated chick biventer cervicis muscle preparation. However, the variable interonium distance, which is believed to range from 11 to 17 Å in these quaternary compounds and is associated with the built in flexibility of these structures about the single bonds on the moieties linked to ring D of the steroid skeleton, resulted in varied degrees of muscle relaxant activity. Some of the compounds also inhibited acetylcholinesterase activity in low concentrations so that they would not be directly suitable for use as muscle relaxants.