RESUMO
A new series of analogues of the calabash curare alkaloid toxiferine I was prepared and pharmacologically evaluated at α7 and muscle-type nAChRs and the allosteric site of muscarinic M2 receptors. The new ligands differ from toxiferine I by the absence of one (2a-c) or two (3a-c) hydroxy groups, saturation of the exocyclic double bonds, and various N-substituents (methyl, allyl, 4-nitrobenzyl). At the muscle-type nAChRs, most ligands showed similar binding to the muscle relaxant alcuronium, indicating neuromuscular blocking activity, with the nonhydroxylated analogues 3b (Ki = 75 nM) and 3c (Ki = 82 nM) displaying the highest affinity. At α7 nAChRs, all ligands showed a moderate to low antagonistic effect, suggesting that the alcoholic functions are not necessary for antagonistic action. Compound 3c exerted the highest preference for the muscle-type nAChRs (Ki = 82 nM) over α7 (IC50 = 21 µM). As for the allosteric site of M2 receptors, binding was found to be dependent on N-substitution rather than on the nature of the side chains. The most potent ligands were the N-allyl analogues 2b and 3b (EC0.5,diss = 12 and 36 nM) and the N-nitrobenzyl derivatives 2c and 3c (EC0.5,diss = 32 and 49 nM). The present findings should help delineate the structural requirements for activity at different types of AChRs and for the design of novel selective ligands.
Assuntos
Receptor Muscarínico M2/química , Toxiferina , Receptor Nicotínico de Acetilcolina alfa7/química , Alcaloides/química , Sítio Alostérico , Humanos , Ligantes , Estrutura Molecular , Músculos/metabolismo , Antagonistas Nicotínicos/farmacologia , Ressonância Magnética Nuclear Biomolecular , Toxiferina/análogos & derivados , Toxiferina/síntese química , Toxiferina/química , Toxiferina/farmacologiaRESUMO
Bisnordihydrotoxiferine, a dimeric tertiary indole alkaloid obtained from the root bark of Strychnos trinervis (Vell.) Mart. (Loganiaceae), inhibited normal defaecation and castor oil, arachidonic acid, and magnesium sulphate-induced diarrhoea on intraperitoneal administration in mice. The effect may be related to the ability of the compound to decrease normal and castor oil-stimulated gastric emptying, small intestinal transit and water and electrolyte accumulation, and inhibition of normal colonic transit. As prostaglandins are involved in gastrointestinal functions, inhibition of their synthesis is likely to contribute to the anticathartic activity, which has never been reported before for an indole alkaloid.
Assuntos
Antidiarreicos/farmacologia , Diarreia/tratamento farmacológico , Toxiferina/análogos & derivados , Animais , Antidiarreicos/isolamento & purificação , Defecação/efeitos dos fármacos , Diarreia/fisiopatologia , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Dose Letal Mediana , Masculino , Camundongos , Potássio/metabolismo , Ratos , Ratos Endogâmicos , Sódio/metabolismo , Toxiferina/isolamento & purificação , Toxiferina/farmacologia , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
Bisnordihydrotoxiferine has been isolated as the major alkaloid from the root bark of Strychnos trinervis. This compound shows a wide antimicrobial spectrum against gram-positive, gram-negative and acid-fast microorganisms, filamentous and yeast-like fungi and also phytopathogenic microorganisms. Preliminary studies also reveal some cytotoxic activity in KB cells which was confirmed by tests against sarcoma 180 tumors.
Assuntos
Alcaloides/análise , Plantas Medicinais/análise , Toxiferina/análogos & derivados , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antibacterianos , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Bactérias/efeitos dos fármacos , Células Cultivadas , Fungos/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Toxiferina/isolamento & purificação , Toxiferina/farmacologiaAssuntos
Acetilcolina/metabolismo , Placa Motora/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Receptores Colinérgicos/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Toxiferina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Autorradiografia , Técnicas In Vitro , Camundongos , Contração Muscular/efeitos dos fármacos , Fatores de TempoRESUMO
Cholinomimetics (pilocarpine, carbachol, physostigmine, acetylcholine, acetyl-beta-methylcholine) and sympathomimetics (dopamine, epinephrine), when injected into the hemolymph, provoked salivary fluid secretion in the female ixodid tick Amblyomma hebraeum Koch. Atropine, but not tubocurarine or toxiferine, abolished pilocarpine-induced secretion without reducing the response to dopamine. Reserpine and guanethidine likewise selectively attenuated pilocarpine-induced secretion. Following extirpation of the synganglion, pilocarpine no longer provoked a secretory response whereas dopamine did. Thus, the salivary gland appears to be innervated directly by catecholaminergic rather than cholinergic secretory nerves. It is suggested that pilocarpine elicits salivation by interacting with muscarinic-type cholinergic receptors situated either on the cell bodies of the secretory nerves, or alternatively in the integrative or sensory pathway.