RESUMEN
Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic agents for intervention in Alzheimer's disease, asthma, cancer, diabetes, and Parkinson's disease. Such compounds also have activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms.
Asunto(s)
Cafeína , Estimulantes del Sistema Nervioso Central/metabolismo , Xantina , Enfermedad de Alzheimer/tratamiento farmacológico , Asma/tratamiento farmacológico , Investigación Biomédica , Cafeína/análogos & derivados , Cafeína/metabolismo , Cafeína/uso terapéutico , Calcio/metabolismo , Estimulantes del Sistema Nervioso Central/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Diuréticos/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Enfermedades Pulmonares/tratamiento farmacológico , Trastornos Mentales/tratamiento farmacológico , Estructura Molecular , Neoplasias/tratamiento farmacológico , Dolor/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Hidrolasas Diéster Fosfóricas/metabolismo , Isoformas de Proteínas/metabolismo , Receptores de GABA-A/metabolismo , Receptores Purinérgicos P1/metabolismo , Xantina/química , Xantina/metabolismo , Xantina/uso terapéuticoRESUMEN
Bufonid toads of the genus Melanophryniscus represent one of several lineages of anurans with the ability to sequester alkaloids from dietary arthropods for chemical defense. The alkaloid profile for Melanophryniscus stelzneri from a location in the province of Córdoba, Argentina, changed significantly over a 10-year period, probably indicating changes in availability of alkaloid-containing arthropods. A total of 29 alkaloids were identified in two collections of this population. Eight alkaloids were identified in M. stelzneri from another location in the province of Córdoba. The alkaloid profiles of Melanophryniscus rubriventris collected from four locations in the provinces of Salta and Jujuy, Argentina, contained 44 compounds and differed considerably between locations. Furthermore, alkaloid profiles of M. stelzneri and M. rubriventris strongly differed, probably reflecting differences in the ecosystem and hence in availability of alkaloid-containing arthropods.
Asunto(s)
Alcaloides/análisis , Animales , Argentina , Artrópodos , Bufonidae , Dieta , Especificidad de la EspecieRESUMEN
Poison frogs of the neotropical family Dendrobatidae contain a wide variety of lipophilic alkaloids, which are accumulated from alkaloid-containing arthropods. A small millipede, Rhinotus purpureus (Siphonotidae), occurs microsympatrically with the dendrobatid frog Dendrobates pumilio on Isla Bastimentos, Bocas del Toro Province, Panamá. Methanol extracts of this millipede contain the spiropyrrolizidine O-methyloxime 236, an alkaloid previously known only from skin extracts of poison frogs, including populations of D. pumilio. Thus, R. purpureus represents a likely dietary source of such alkaloids in dendrobatid frogs.
Asunto(s)
Alcaloides/farmacocinética , Artrópodos/química , Ranidae , Animales , DietaRESUMEN
Australian myobatrachid frogs of the genus Pseudophryne have only two classes of alkaloids in skin extracts, pseudophrynamines (PSs) and pumiliotoxins (PTXs). The former are unique to such Australian frogs, while the PTXs occur worldwide in all other genera of frogs/toads that contain lipophilic alkaloids. The major alkaloid of wild-caught frogs from one population of Pseudophryne semimarmorata was PTX 267C, while PSs were only minor or trace alkaloids. Captive-raised frogs from the same parental stock had no PTXs, but had larger amounts of PSs. A PTX fed to captive-raised frogs accumulated into skin along with dihydro and hydroxy metabolites. Thus, Pseudophryne frogs appear to biosynthesize PSs, but to sequester into skin dietary PTXs. In addition, biosynthesis of PSs appears reduced when high levels of dietary PTXs have accumulated into skin. This is the first evidence indicating that certain frogs are capable of synthesizing rather than merely sequestering alkaloids. A wide range of PSs, including many with molecular weights >500, were detected using both GC-mass spectral and LC-mass spectral analysis.
Asunto(s)
Alcaloides/biosíntesis , Venenos de Anfibios/biosíntesis , Piel/química , Alcaloides/síntesis química , Alcaloides/química , Alcaloides/farmacología , Venenos de Anfibios/química , Venenos de Anfibios/clasificación , Venenos de Anfibios/farmacología , Animales , Anuros , Australia , Femenino , Cromatografía de Gases y Espectrometría de Masas , Indoles/química , Insectos , Masculino , Estructura MolecularRESUMEN
Chemical ionization tandem mass spectrometry (CI-MS/MS) of alkaloids with ammonia reagent gas and collision-activated dissociation as well as EI-MS/MS were applied to the tetraponerine alkaloids in extracts from six pseudomyrmecine ants of the genus Tetraponera. The MS/MS techniques along with gas chromatography Fourier transform infrared (GC/FTIR) spectra allowed identification in two extracts of seven of the eight known tetraponerines. The EI-MS/MS fragmentations proved diagnostic for the ring system and the CI-MS/MS patterns for the C-8 or C-9 substitution, while the Bohlmann bands in FTIR spectra were diagnostic for the C-8 or C-9 configurations. An Indian ant (T. allaborans) had T-2, T-4 and T-8, while a Chinese ant (T. binghami) had T-5, T-6, T-7 and T-8. Four other ants, T. rufonigra (India), T. penzigi (Africa), T. clypeata (Africa) and T. sp. cf. emeryi (Africa), had no tetraponerines.
Asunto(s)
Alcaloides/química , Hormigas , Alcaloides/aislamiento & purificación , Animales , Cromatografía de Gases/métodos , Espectrometría de Masas/métodos , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectroscopía Infrarroja por Transformada de Fourier/métodosRESUMEN
The principal alkaloid 275A in skins of the Colombian poison frog Dendrobates lehmanni has been identified as the pyrrolo[1,2-a]azepane (1), the first occurrence in nature of this "izidine" system. Tetrahydro-1 proved identical to one of the four synthetic diastereomers, 2a--2d, thereby establishing that 1 has the 5Z,10E relative stereochemistry. Alkaloid 1 is often accompanied by other congeners, in particular a 5Z,10Z diastereomer 15, a dihydro analogue 16, and a ketone 17. Such izidines in frogs may arise from dietary ants, as do other classes of izidines.
Asunto(s)
Alcaloides/química , Compuestos Aza/química , Compuestos Bicíclicos con Puentes/química , Alcaloides/síntesis química , Animales , Anuros , Compuestos Aza/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Cromatografía de Gases , Estructura Molecular , Análisis Espectral , EstereoisomerismoRESUMEN
Caffeine has been used as a pharmacological tool to study the ryanodine receptor (RYR)-mediated Ca2+ release from caffeine-sensitive, inositol 1,4,5,-trisphosphate (IP3)-insensitive pools. In the present study, we demonstrate multiple effects of caffeine on Ca2+ homeostasis in human B lymphocytes. Although B cells express a functional RYR, which can be activated by 4-chloro-m-cresol following depletion of IP(3)-sensitive pools, caffeine does not activate RYR-mediated Ca2+ release. Instead, caffeine dose-dependently inhibited IP3 receptor (IP3R)-mediated Ca2+ release, RYR-mediated Ca2+ release and B cell receptor-initiated Ca2+ influx, while high concentrations of caffeine (> or = 25 mM) induced a Ca2+ influx. In contrast with its ability to suppress receptor-stimulated Ca2+ influx, caffeine had no significant effect on the store-operated Ca2+ (SOC) channel-dependent Ca2+ influx induced by thapsigargin. Thus, caffeine may act as an inhibitor on a single or multiple site(s) responsible for regulating the IP3R channel, RYR channel and presumably the receptor-mediated SOC channel. The present report may be the first demonstration of multiple effects of caffeine on Ca2+ mobilization in single cell type. Our results suggest the need for caution regarding use of caffeine simply as a RYR-activator to study Ca2+ homeostasis in eucaryotic cells.
Asunto(s)
Linfocitos B/metabolismo , Cafeína/farmacología , Calcio/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Humanos , Transporte Iónico/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Batrachotoxins, including many congeners not previously described, were detected, and relative amounts were measured by using HPLC-mass spectrometry, in five species of New Guinean birds of the genus Pitohui as well as a species of a second toxic bird genus, Ifrita kowaldi. The alkaloids, identified in feathers and skin, were batrachotoxinin-A cis-crotonate (1), an allylically rearranged 16-acetate (2), which can form from 1 by sigmatropic rearrangement under basic conditions, batrachotoxinin-A and an isomer (3 and 3a, respectively), batrachotoxin (4), batrachotoxinin-A 3'-hydroxypentanoate (5), homobatrachotoxin (6), and mono- and dihydroxylated derivatives of homobatrachotoxin. The highest levels of batrachotoxins were generally present in the contour feathers of belly, breast, or legs in Pitohui dichrous, Pitohui kirhocephalus, and Ifrita kowaldi. Lesser amounts are found in head, back, tail, and wing feathers. Batrachotoxin (4) and homobatrachotoxin (6) were found only in feathers and not in skin. The levels of batrachotoxins varied widely for different populations of Pitohui and Ifrita, a result compatible with the hypothesis that these birds are sequestering toxins from a dietary source.
Asunto(s)
Alcaloides/aislamiento & purificación , Batracotoxinas/aislamiento & purificación , Plumas/química , Pájaros Cantores , Alcaloides/química , Animales , Batracotoxinas/química , Cromatografía Líquida de Alta Presión , Espectrometría de Masas , Estructura Molecular , Nueva Guinea , Pájaros Cantores/clasificación , Especificidad de la EspecieRESUMEN
An alternative asymmetric synthesis of (+)-(lS,9aS)-homopumiliotoxin 223G (1) was accomplished via (1R,2R, 9aS)-1-(benzyloxy)-2-hydroxy-1-methyl-3[(E)-isobutylidene]++ +quinolizidi ne (4), which was synthesized according to the intramolecular nickel(II)/chromium(II)-mediated cyclization of the N-(iodoalkenyl)aldehyde 2. Compound 4 was converted to the acetate and subjected to reduction with lithium in ammonia, whereupon deprotection of the O-benzyl group and removal of the acetoxyl group occurred in a single operation to afford (+)-homopumiliotoxin 223G. The same sequence using (+/-)-4 was applied to the synthesis of racemic 223G. Gas chromatography of a sample of racemic 223G showed no separation into enantiomers on four different cyclodextrin-based chiral GC columns. We found, however, that the O-acetates of (+/-)-223G gave a nearly baseline separation on either a beta-cyclodextrin column or a permethylated beta-cyclodextrin column. The O-acetate of synthetic (+)-223G was identical on either of these two columns, with the first eluting O-acetate from acetylated (+/-)-223G and also with the acetylated 223G present in a frog skin extract, thus allowing us to confirm unambiguously the 1S,9aS absolute configurations of natural 223G.
Asunto(s)
Alcaloides/síntesis química , Indolizinas , Toxinas Marinas/síntesis química , Piperidinas , Alcaloides/química , Animales , Anuros , Cromatografía de Gases , Cromatografía en Gel , Ciclodextrinas/química , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia Magnética , Toxinas Marinas/química , EstereoisomerismoRESUMEN
Loperamide is a widely used antidiarrheal that primarily acts at nanomolar concentrations through activation of opioid receptors in the gastrointestinal tract. At somewhat higher concentrations, loperamide blocks calmodulin activity, calcium channels, N-methyl-D-aspartate-receptor channels, and maitotoxin-elicited calcium influx. Loperamide at micromolar concentrations has now been shown to have a remarkable stimulatory effect on the capacitative calcium influx that is triggered in many cells by depletion of the inositol-trisphosphate-sensitive stores of calcium in the endoplasmic reticulum. The mechanism whereby loperamide enhances levels of intracellular calcium elevated by capacitative calcium influx is, as yet, undefined.
Asunto(s)
Calcio/metabolismo , Loperamida/farmacología , Adenosina Trifosfato/farmacología , Animales , Antidiarreicos/administración & dosificación , Antidiarreicos/química , Antidiarreicos/farmacología , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Sistema Digestivo/citología , Sistema Digestivo/efectos de los fármacos , Sistema Digestivo/metabolismo , Conductividad Eléctrica , Humanos , Loperamida/administración & dosificación , Loperamida/químicaRESUMEN
A series of esters of 6beta-hydroxynortropane and the N-methyl analogue 6beta-tropanol were synthesized and screened versus binding of an antagonist (quinuclidinyl benzilate) and an agonist (oxotremorine-M) at sites on human m(1)-, m(2)-, m(3)-, and m(4)-muscarinic receptors in transfected cell membranes and on native M(1)-muscarinic receptors in rat brain membranes and native M(2)-muscarinic receptors in rat heart membranes. Most 6beta-acyloxy(nor)tropanes had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at transfected m(1)- and native M(1)-receptors, indicative of agonist activity. 6beta-Acetoxynortropane had K(i) values versus oxotremorine-M binding at m(1)-, m(2)-, and m(4)-receptors ranging from 4 to 7 nM. N-Methylation reduced affinity greatly as did increasing the size of the acyl moiety. The affinity of 6beta-benzoyloxynortropane and other analogues with larger acyl moieties was little affected by N-methylation or in some cases was increased. 6beta-Acyloxy(nor)tropanes and classical muscarinic agonists, such as muscarine and oxotremorine, had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at native M(2)-muscarinic receptors of heart, but not at transfected m(2)-muscarinic receptors. Antagonist/agonist binding ratios were not obtained for transfected m(3)-receptors, since significant oxotremorine-M binding could not be detected. 6beta-Acyloxy(nor)tropane, two other (nor)tropanes, and the classical muscarinic agonists had higher affinity versus agonist binding compared to antagonist binding for transfected m(4)-receptors. The antagonist/agonist binding ratio method is clearly not always reliable for predicting agonist activity at muscarinic receptors.
Asunto(s)
Agonistas Muscarínicos/síntesis química , Receptores Muscarínicos/efectos de los fármacos , Tropanos/síntesis química , Inhibidores de Adenilato Ciclasa , Animales , Sitios de Unión , Células CHO , Corteza Cerebral/metabolismo , Cricetinae , Humanos , Técnicas In Vitro , Agonistas Muscarínicos/química , Agonistas Muscarínicos/metabolismo , Agonistas Muscarínicos/farmacología , Miocardio/metabolismo , Oxotremorina/análogos & derivados , Oxotremorina/metabolismo , Quinuclidinil Bencilato/metabolismo , Ratas , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Receptor Muscarínico M3 , Receptor Muscarínico M4 , Receptores Muscarínicos/metabolismo , Transfección , Tropanos/química , Tropanos/metabolismo , Tropanos/farmacologíaRESUMEN
Sphingosine induces a biphasic increase in cytosolic-free Ca(2+)([Ca(2+)](i)) with an initial peak followed by a sustained increase in HL-60 cells differentiated into neutrophil-like cells. The initial peak is not affected by the presence of ethylene glycol bis (beta-aminoethyl ether) N, N, N', N-tetraacetic acid (EGTA) in the buffer and appears to be dependent on conversion of sphingosine to sphingosine -1-phosphate (S1P) by sphingosine kinase, since it is blocked by the presence of N, N-dimethylsphingosine (DMS), which, like sphingosine, causes a sustained increase itself. The sustained increase that is elicited by sphingosine or DMS is abolished by the presence of EGTA in the buffer. The sustained sphingosine-induced Ca(2+)influx does not appear due to Ca(2+)influx through store-operated Ca(2+)(SOC) channels, since the influx is not inhibited by SKF 96365, nor is it augmented by loperamide. In addition, sphingosine and DMS attenuate the Ca(2+)influx through SOC channels that occurs after depletion of intracellular stores by ATP or thapsigargin. Both the initial peak and the sustained increase in [Ca(2+)](i)elicited by sphingosine can be blocked by phorbol 12-myristate 13-acetate (PMA)-elicited activation of protein kinase C. Thus, in HL-60 cells sphingosine causes a mobilization of Ca(2+)from intracellular Ca(2+)stores, which requires conversion to S1P, while both sphingosine and DMS elicit a Ca(2+)influx through an undefined Ca(2+)channel and cause a blockade of SOC channels.
Asunto(s)
Señalización del Calcio/efectos de los fármacos , Calcio/metabolismo , Células HL-60/efectos de los fármacos , Lisofosfolípidos , Esfingosina/análogos & derivados , Esfingosina/farmacología , Canales de Calcio/efectos de los fármacos , Canales de Calcio/fisiología , Señalización del Calcio/fisiología , Células HL-60/fisiología , Humanos , Fosfotransferasas (Aceptor de Grupo Alcohol)/farmacología , Esfingosina/metabolismoRESUMEN
The structure-activity relationships of calmidazolium analogs with respect to intracellular calcium levels were investigated in HL-60 cells. Quaternized derivatives of miconazole and clotrimazole, known inhibitors of store-operated calcium (SOC) channels, were synthesized. The quaternary N-methyl derivatives of miconazole (3) and clotrimazole (6) had no effect on intracellular calcium levels, alone or after elevation of calcium induced by ATP. Calmidazolium alone induced a large increase in intracellular calcium levels in HL-60 cells (EC(50) 3 microM). Similar effects were observed for miconazole derivatives 1 (EC(50) 15 microM) and 2 (EC(50) 10 microM), wherein the diphenylmethyl group in calmidazolium was replaced by a 3,5-difluorobenzyl or cyclohexylmethyl group, respectively. The analogous clotrimazole derivatives 4 and 5 had no effect on intracellular calcium levels. The elevation of calcium levels by calmidazolium, 1, and 2 appears to be comprised of a calcium release component from inositol trisphosphate (IP(3))-sensitive stores followed by a large calcium influx component. Calcium influx was greater than that normally observed due to depletion of IP(3)-sensitive calcium stores and activation of SOC channels. In addition, only a small component of the calmidazolium-elicited influx was inhibited by the SOC channel blocker miconazole. Thus, certain quaternized imidazoles substituted with large residues at both nitrogens of the imidazole ring caused both release and influx of calcium, the latter in part through SOC channels but mainly through an undefined cationic channel. Quaternized imidazoles, unlike the parent nonquaternary imidazole miconazole, did not block SOC channels. Inhibitory effects on calmodulin-activated phosphodiesterase did not correlate with effects on calcium release and influx.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Calcio/metabolismo , Imidazoles/farmacología , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Antifúngicos/farmacología , Bloqueadores de los Canales de Calcio/química , Calmodulina/antagonistas & inhibidores , Células HL-60 , Humanos , Imidazoles/química , Fosfatos de Inositol/metabolismo , Miconazol/farmacologíaRESUMEN
(1) The methylxanthine caffeine has many pharmacological effects, most of which can be linked to blockade of adenosine receptors, inhibition of phosphodiesterases, and augmentation of calcium-dependent release of calcium from intracellular stores. (2) A variety of xanthines have been developed as potent and/or selective antagonists for adenosine receptors. (3) Several xanthines have been developed that are more potent and more selective inhibitors of cyclic nucleotide phosphodiesterase than caffeine or theophylline. (4) Caffeine remains the xanthine of choice for activation of intracellular calcium-sensitive calcium release channels although millimolar concentrations are required, which can have effects on other aspects of calcium regulation.
Asunto(s)
Xantinas , Animales , Calcio/fisiología , Humanos , Canales Iónicos/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/fisiología , Receptores Purinérgicos P1/efectos de los fármacos , Xantinas/farmacologíaAsunto(s)
Alcaloides/aislamiento & purificación , Analgésicos no Narcóticos/aislamiento & purificación , Compuestos Bicíclicos Heterocíclicos con Puentes/aislamiento & purificación , Diseño de Fármacos , Agonistas Nicotínicos/aislamiento & purificación , Piridinas/aislamiento & purificación , Piel/química , Alcaloides/síntesis química , Alcaloides/química , Analgésicos no Narcóticos/química , Analgésicos no Narcóticos/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Humanos , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/química , Piridinas/síntesis química , Piridinas/química , RanidaeRESUMEN
Caffeine inhibits the G2 checkpoint activated by DNA damage and enhances the toxicity of DNA-damaging agents towards p53-defective cancer cells. The relationship between structure and G2 checkpoint inhibition was determined for 56 caffeine analogs. Replacement of the methyl group at position 3 or 7 resulted in loss of activity, while replacement at position 1 by ethyl or propyl increased activity slightly. 8-Substituted caffeines retained activity, but were relatively insoluble. The structure-activity profile did not resemble those for other known pharmacological activities of caffeine. The active analogs also potentiated the killing of p53-defective cells by ionizing radiation, but none was as effective as caffeine.
Asunto(s)
Cafeína/análogos & derivados , Reparación del ADN/efectos de los fármacos , Fase G2/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Cafeína/química , Radioisótopos de Cobalto , Daño del ADN , Humanos , Relación Estructura-Actividad , Células Tumorales Cultivadas/efectos de la radiación , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Several routes to the enantiomers of fluoronorepinephrines (1) and fluoroepinephrines (2) were explored. A catalytic enantioselective oxazaborolidine reduction and a chiral (salen)Ti(IV) catalyzed asymmetric synthesis of silyl cyanohydrins proved efficacious in the key stereo-defining steps of two respective routes. Binding studies of the catecholamines with alpha(1)-, alpha(2)-, beta(1)-, and beta(2)-adrenergic receptors were examined. The assays confirmed that fluorine substitution had marked effects on the affinity of (R)-norepinephrine and (R)-epinephrine for adrenergic receptors, depending on the position of substitution. Thus, a fluoro substituent at the 2-position of (R)-norepinephrine and (R)-epinephrine reduced activity at both alpha(1)- and alpha(2)-receptors and enhanced activity at beta(1)- and beta(2)-receptors, while fluorination at the 6-position reduced activity at the beta(1)- and beta(2)-receptors. The effects of fluorine substitution on the S-isomers were less predictable.
Asunto(s)
Epinefrina/análogos & derivados , Norepinefrina/análogos & derivados , Agonistas Adrenérgicos beta/síntesis química , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/metabolismo , Animales , Unión Competitiva , Cerebelo/metabolismo , Corteza Cerebral/metabolismo , Epinefrina/síntesis química , Epinefrina/química , Epinefrina/metabolismo , Técnicas In Vitro , Norepinefrina/síntesis química , Norepinefrina/química , Norepinefrina/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The effect of temperature on calcium release and influx has been compared in differentiated and undifferentiated HL-60 cells. Receptor-mediated release of intracellular calcium by ATP was little affected by temperature in HL-60 cells. In differentiated HL-60 cells the store-operated calcium (SOC) channel-dependent sustained elevation of calcium levels after ATP was maximal at 25-29 degrees C; at higher temperatures calcium levels returned relatively rapidly towards basal levels. In undifferentiated cells, a SOC channel-dependent sustained elevation of calcium levels was not observed with levels returning to basal levels much more rapidly than in differentiated cells. The initial thapsigargin-initiated elevation of calcium did not become maximal until about 25 degrees C in both differentiated and undifferentiated HL-60 cells. In differentiated cells, the SOC channel-dependent sustained elevation of calcium after thapsigargin was maximal at 30-37 degrees C, while in undifferentiated cells, the sustained elevation was maximal at 25-30 degrees C. Loperamide, which augments the SOC channel-dependent sustained elevation of calcium, showed a temperature-dependent response that was maximal at about 22 degrees C after either ATP or thapsigargin and was minimal at 37 degrees C. In contrast, inhibition of SOC channel-dependent elevation of calcium by miconazole or trifluoperazine was not greatly affected by temperature.
Asunto(s)
Canales de Calcio/metabolismo , Loperamida/farmacología , Adenosina Trifosfato/farmacología , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Quelantes/farmacología , Ácido Egtácico/farmacología , Inhibidores Enzimáticos/farmacología , Células HL-60 , Humanos , Temperatura , Tapsigargina/farmacologíaRESUMEN
An efficient, high-yield stereospecific route to three (+/-)-5, 8-disubstituted indolizidines, (209B (I), 209I (II), 223J (III)) and two (+/-)-1,4-disubstituted quinolizidines (207I (IV), 233A (V)), racemates of alkaloids found in the skins of neotropical and Madagascan poison frogs is reported. The structures of the natural alkaloids were thereby established by chiral GC comparison with the exception of indolizidine 209B (I) for which a natural 209B could no longer be detected.
Asunto(s)
Animales Ponzoñosos , Indolizinas/síntesis química , Quinolizinas/síntesis química , Ranidae , Piel/química , Alquilación , Animales , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Oxidación-Reducción , Espectrofotometría Infrarroja , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
1. Chronic ingestion of caffeine causes a significant increase in levels of A1-adenosine, nicotinic and muscarinic receptors, serotonergic receptors, GABAA receptors and L-type calcium channels in cerebral cortical membranes from mice NIH Swiss strain mice. 2. Chronic theophylline and paraxanthine had effects similar to those of caffeine except that levels of L-type channels were unchanged. Chronic theobromine, a weak adenosine antagonist, and 1-isobutyl-3-methylxanthine (IBMX), a potent adenosine antagonist and phosphodiesterase inhibitor, caused only an increase in levels of A1-adenosine receptors. A combination of chronic caffeine and IBMX had the same effects on receptors as caffeine alone. Chronic 3,7-dimethyl-1-propargylxanthine (DMPX), a somewhat selective A2A-antagonist, caused only an increase in levels of A1-adenosine receptors. Pentoxifylline, an adenosine-uptake inhibitor inactive at adenosine receptors, had no effect on receptor levels or calcium channels. 3. A comparison of plasma and brain levels of xanthines indicated that caffeine penetrated more readily and attained somewhat higher brain levels than theophylline or theobromine. Penetration and levels were even lower for IBMX, paraxanthine, DMPX, and pentoxyfylline. 4. The results suggest that effective blockade of both A1 and A2A-adenosine receptors is necessary for the full spectrum of biochemical changes elicited by chronic ingestion of xanthines, such as caffeine, theophylline, and paraxanthine.