RESUMO
The European Pharmacopoeia (Ph. Eur.) described two separate HPLC methods for determination of organic impurities in oxitropium bromide, a synthetic anticholinergic agent used by inhalation in the treatment of asthma and other bronchial disorders, and a potentiometric titration assay method which is not a stability indicating method. During synthetic process development and analytical studies of oxitropium; besides known Ph. Eur.-impurities new process related and degradation impurities were determined, identified by LC-MS, synthesized, characterized, and then used in development and validation studies of oxitropium analytical methods. As a result of these studies, a single HPLC related substances method was developed and validated according to international conference on harmonisation (ICH) guidelines for determination of all oxitropium related substances by using an inertsil ODS-4 (250 mm × 4.6 mm, 5 µm) column at 15 °C with 50 µL injection volume at a wavelength of 210 nm with gradient elution of phosphate-buffer/acetonitrile mixture flowing at a rate of 1.2 mL/min during 60 min. Also, a stability indicating HPLC assay method was developed and validated by using an XBridge C18 (150 mm × 4.6 mm, 3.5 µm) column at 25 °C with 10 µL injection volume at a wavelength of 210 nm and with phosphate-buffer/acetonitrile (85/15) mixture flowing at a rate of 1.0 mL/min during 10 min. Stress-testing and stability studies of oxitropium bromide was carried out and samples were analyzed by using newly developed stability-indicating HPLC assay and related substances methods.
Assuntos
Derivados da Escopolamina/química , Derivados da Escopolamina/síntese química , Cromatografia Líquida de Alta Pressão/métodos , Contaminação de Medicamentos , Estabilidade de Medicamentos , Espectrometria de Massas/métodos , Reprodutibilidade dos TestesRESUMO
Bivalent ligands of G protein-coupled receptors have been shown to simultaneously either bind to two adjacent receptors or to bridge different parts of one receptor protein. Recently, we found that bivalent agonists of muscarinic receptors can simultaneously occupy both the orthosteric transmitter binding site and the allosteric vestibule of the receptor protein. Such dualsteric agonists display a certain extent of subtype selectivity, generate pathway-specific signaling, and in addition may allow for designed partial agonism. Here, we want to extend the concept to bivalent antagonism. Using the phthal- and naphthalimide moieties, which bind to the allosteric, extracellular site, and atropine or scopolamine as orthosteric building blocks, both connected by a hexamethonium linker, we were able to prove a bitopic binding mode of antagonist hybrids for the first time. This is demonstrated by structure-activity relationships, site-directed mutagenesis, molecular docking studies, and molecular dynamics simulations. Findings revealed that a difference in spatial orientation of the orthosteric tropane moiety translates into a divergent M2/M5 subtype selectivity of the corresponding bitopic hybrids.
Assuntos
Derivados da Atropina/química , Antagonistas Muscarínicos/química , Naftalimidas/química , Ftalimidas/química , Derivados da Escopolamina/química , Regulação Alostérica , Animais , Derivados da Atropina/síntese química , Derivados da Atropina/farmacologia , Sítios de Ligação , Células CHO , Cricetulus , Agonismo Inverso de Drogas , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Agonistas Muscarínicos/síntese química , Agonistas Muscarínicos/química , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacologia , Mutação , Naftalimidas/síntese química , Naftalimidas/farmacologia , Ftalimidas/síntese química , Ftalimidas/farmacologia , Ensaio Radioligante , Receptor Muscarínico M2/agonistas , Receptor Muscarínico M2/antagonistas & inibidores , Receptor Muscarínico M2/genética , Derivados da Escopolamina/síntese química , Derivados da Escopolamina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
-Anisodine (l-6,7-epoxy-3-tropyl-alpha-hydroxytropate), which was isolated from the medicinal plant Scopolia tanguticus Maxim, was the first efficiently prepared using 6-beta-acetyltropine as the starting material via a key step of the Sharpless asymmetric dihydroxylation (AD). The intermediate compounds 10 and 11 showed promising cholinergic activity.
Assuntos
Derivados da Escopolamina/química , Derivados da Escopolamina/síntese química , Animais , Antagonistas Colinérgicos/síntese química , Antagonistas Colinérgicos/química , Cobaias , Hidroxilação , Íleo/efeitos dos fármacos , Estrutura Molecular , Estereoisomerismo , Tropanos/químicaRESUMO
Concepts involved in the design of soft drugs (drugs which, after achieving their therapeutic role, are metabolized in a predictable manner and at a controlled rate to non-toxic moieties) have been applied to methscopolamine. Selected aliphatic and cycloaliphatic esters (4a-e) of a hypothetical metabolite (2a) of methscopolamine with a phenylsuccinic acid basic structural moiety were designed and found to have anticholinergic activity and to revert to the original hypothetical metabolite in biological media with fairly short half lives. The pA2 values of the soft drugs were determined and the hypothetical metabolite was found 100 times less potent than the most potent compound (4a) of the series. The anticholinergic activities were found to be dependent on the length of the side chain alcohol.
Assuntos
Desenho de Fármacos , Parassimpatolíticos/síntese química , Derivados da Escopolamina/síntese química , Animais , Avaliação de Medicamentos , Estabilidade de Medicamentos , Cobaias , Humanos , Técnicas In Vitro , Parassimpatolíticos/química , Parassimpatolíticos/farmacologia , Coelhos , Ratos , Derivados da Escopolamina/química , Derivados da Escopolamina/farmacologia , Relação Estrutura-AtividadeRESUMO
Concepts involved in the design of soft drugs (drugs which, after achieving their therapeutic role, are metabolized in a predictable manner and at a controlled rate to non-toxic moieties) have been applied to methscopolamine (1). Selected aliphatic and cycloaliphatic esters (3) of a hypothetical carboxylic acid metabolite (2) of methscopolamine were designed and found to have anticholinergic activity. Six soft drug analogs of methscopolamine were tested for mydriatic activity in rabbit eye. At equieffective doses, the AUC24 hrs and the mydriatic recovery time were found to be significantly less with some of the soft drugs compared to methscopolamine and soft drug 3a was found to be shorter acting than tropicamide. At equieffective doses the AUC24 hrs for soft drugs ranged from 23.2% to 187% of that of methscopolamine. Significant dilation of the untreated eye was observed with scopolamine but not with the soft drugs after unilateral administration. Soft drug 3a exhibited only 2.3% of the AUC6 hrs (untreated eye) of that of methscopolamine.
Assuntos
Desenho de Fármacos , Parassimpatolíticos/síntese química , Derivados da Escopolamina/síntese química , Animais , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Cobaias , Técnicas In Vitro , Masculino , Parassimpatolíticos/química , Parassimpatolíticos/farmacologia , Pupila/efeitos dos fármacos , Coelhos , Derivados da Escopolamina/química , Derivados da Escopolamina/farmacologiaRESUMO
Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.
Assuntos
Amidinas/farmacologia , Derivados da Atropina/farmacologia , Muscarina/antagonistas & inibidores , Derivados da Escopolamina/farmacologia , Amidinas/síntese química , Amidinas/metabolismo , Animais , Derivados da Atropina/síntese química , Derivados da Atropina/metabolismo , Cátions , Córtex Cerebral/metabolismo , Fenômenos Químicos , Química , Físico-Química , Eletroquímica , Feminino , Masculino , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Miocárdio/metabolismo , Parassimpatolíticos/farmacologia , Ratos , Ratos Endogâmicos , Receptores Muscarínicos/metabolismo , Salivação/efeitos dos fármacos , Derivados da Escopolamina/síntese química , Derivados da Escopolamina/metabolismo , Glândula Submandibular/metabolismoRESUMO
A synthesis of [11C]scopolamine capable of clinical delivery of this agent in high specific activity is described. The precursor [11C]formaldehyde was produced by catalytic oxidation of [11C]CH3OH over metallic silver and was used to N-11C-methylate norscopolamine using aqueous neutral potassium phosphite as the reducing agent. The labeling reaction was complete after 5 min at 75-80 degrees C and the [11C]scopolamine (99% radiochemical purity) was isolated by preparative HPLC. Total synthesis time is less than 45 min. Decay corrected radiochemical yields from [11C]CO2 are presently 20-43%.
Assuntos
Radioisótopos de Carbono , Parassimpatolíticos/síntese química , Fosfitos , Compostos de Potássio , Derivados da Escopolamina/síntese química , Formaldeído , Humanos , Marcação por Isótopo/métodos , N-Metilescopolamina , Ácidos Fosforosos , Receptores Muscarínicos , Tomografia Computadorizada de EmissãoRESUMO
The pharmacology and clinical use of cimetropium bromide is reviewed. Experimental and clinical data demonstrated that this new compound is a potent antimuscarinic and an effective antispasmodic drug. It is also endowed of a direct myolitic action which partially accounts for its antispasmodic activity. Clinical trials as yet performed confirmed its efficacy in many painful conditions of the gastrointestinal, biliary and genitourinary tracts, as well as its usefulness as a pre-endoscopic medication. Finally, the drug proved to be well tolerated, with a low incidence of atropine-like untoward effects.
Assuntos
Parassimpatolíticos/farmacologia , Derivados da Escopolamina/farmacologia , Animais , Antiulcerosos , Atropina/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Motilidade Gastrointestinal/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Cinética , Contração Muscular/efeitos dos fármacos , Parassimpatolíticos/síntese química , Parassimpatolíticos/metabolismo , Parassimpatolíticos/uso terapêutico , Parassimpatolíticos/toxicidade , Pupila/efeitos dos fármacos , Salivação/efeitos dos fármacos , Derivados da Escopolamina/síntese química , Derivados da Escopolamina/metabolismo , Derivados da Escopolamina/uso terapêutico , Derivados da Escopolamina/toxicidadeRESUMO
The synthesis of anticholinergic N-alkylnorscopolamines and their quaternary salts, especially the synthesis of (-)-N-ethylnorscopolamin methobromide (Ba 253 BR), is reported. (-)-N-Ethylnorscopolamine methobromide differs from the stereoisomeric (-)-N-ethylscopolammonium bromide not only by its physico-chemical, but also by its pharmacological properties. (-)-N-Ethylnorscopolamine methobromide represents an anticholinergic bronchodilator with long duration of action.