RESUMEN
The disulfide functionality is present in a number of organic compounds of interest in the fields of both chemistry and biology. Because the disulfide group is known to be highly susceptible to further oxidation by a wide range of agents, performing a chemoselective oxidation without further oxidizing the disulfide moiety poses a synthetic challenge. Reported herein are the first examples of such a chemoselective oxidation in which a series of novel secondary alcohol disulfides 2a-f have been converted to the corresponding symmetrical diketones 3a-f utilizing a modified Swern oxidation.
Asunto(s)
Alcoholes/química , Cetonas/química , Disulfuros/química , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Oxidación-ReducciónRESUMEN
Nonsteroidal anti-inflammatory drugs (NSAIDs) have unacceptable morbidity and mortality due to their gastrointestinal toxicity. Attempts so far to improve the safety profile of NSAIDs have met with limited clinical acceptance. Nitric oxide (NO) functions as an endogenous mediator of gastric mucosal health and defense. Recent medicinal chemistry approaches attempt to exploit the tissue-protective function of NO against NSAID-induced gastric injury. Both nitroxybutyl-ester and nitrosothiol NSAID derivatives have been synthesized. Profiling of these NO-donating NSAIDs in both the laboratory and the clinic suggests that they might offer a unique solution to the problem of NSAID-induced gastropathy without sacrificing the well-accepted pharmacological activity of these agents in the management of pain and inflammation.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Fenómenos Fisiológicos del Sistema Digestivo , Mucosa Gástrica/patología , Mucosa Intestinal/patología , Donantes de Óxido Nítrico/síntesis química , Óxido Nítrico/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/toxicidad , Sistema Digestivo/efectos de los fármacos , Sistema Digestivo/patología , Diseño de Fármacos , Mucosa Gástrica/efectos de los fármacos , Humanos , Mucosa Intestinal/efectos de los fármacos , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Relación Estructura-ActividadRESUMEN
Despite its widespread use, diclofenac has gastrointestinal liabilities common to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced by concomitant administration of a gastrointestinal cytoprotectant such as nitric oxide (NO). A series of novel diclofenac esters containing a nitrosothiol (-S-NO) moiety as a NO donor functionality has been synthesized and evaluated in vivo for bioavailability, pharmacological activity, and gastric irritation. All S-NO-diclofenac derivatives acted as orally bioavailable prodrugs, producing significant levels of diclofenac in plasma within 15 min after oral administration to mice. At equimolar oral doses, S-NO-diclofenac derivatives (20a-21b) displayed rat antiinflammatory and analgesic activities comparable to those of diclofenac in the carrageenan-induced paw edema test and the mouse phenylbenzoquinone-induced writhing test, respectively. All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in that they elicited markedly fewer stomach lesions as compared to the stomach lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosothiol esters of diclofenac comprise a novel class of NO-donating compounds having therapeutic potential as nonsteroidal antiinflammatory agents with an enhanced gastric safety profile.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Diclofenaco/síntesis química , Compuestos Nitrosos/síntesis química , Profármacos/síntesis química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Disponibilidad Biológica , Diclofenaco/química , Diclofenaco/farmacocinética , Diclofenaco/farmacología , Masculino , Ratones , Compuestos Nitrosos/química , Compuestos Nitrosos/farmacocinética , Compuestos Nitrosos/farmacología , Profármacos/química , Profármacos/farmacocinética , Profármacos/farmacología , Ratas , Ratas Sprague-Dawley , Estómago/patología , Relación Estructura-ActividadRESUMEN
Two studies were conducted to assess, in vivo, potential anti-nicotinic effects of the iboga alkaloid ibogaine and its synthetic congener 18-methoxycoronaridine (18-MC). As previously demonstrated for ibogaine, using microdialysis, pretreatment (19h beforehand) with 18-MC (40 mg/kg, i.p.) significantly attenuated nicotine-induced dopamine release in the nucleus accumbens of awake and freely moving rats. In an oral model of nicotine self-administration, both ibogaine and 18-MC decreased rats' preferences for nicotine for at least 24 h. Acutely, during the first hour after administration, ibogaine depressed responding for water as well as for nicotine; however, during this same time, 18-MC reduced nicotine intake without affecting responding for water. The results suggest that 18-MC might be the prototype of a new treatment for smoking.
Asunto(s)
Dopamina/metabolismo , Ibogaína/análogos & derivados , Nicotina/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Análisis de Varianza , Animales , Discriminación en Psicología/efectos de los fármacos , Ácido Homovanílico/metabolismo , Ibogaína/farmacología , Ibogaína/uso terapéutico , Masculino , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Autoadministración , Fumar/tratamiento farmacológicoRESUMEN
We previously reported that single administration of ibogaine, an indol alkaloid with antiaddictive properties, dose dependently reduced alcohol intake in three strains of alcohol-preferring rats. The present study examined the effect of different doses of a newly developed nontoxic ibogaine analogue, 18-methoxycoronaridine (18-MC), on alcohol intake. Selectively bred alcohol-preferring rats received a single intraperitoneal injection of vehicle or 5, 20 and 40 mg/kg of 18-MC at 9:30 AM, and their consumption of alcohol, water and food was measured for 24 h. Our results demonstrate that a single injection of 18-MC significantly and dose dependently attenuated alcohol consumption and preference and commensurately increased water intake. Only the highest dose of 18-MC significantly decreased food intake. Although the true mechanism of action of 18-MC in suppressing alcohol intake is not yet fully understood, it may, like ibogaine, exert its attenuating effects on alcohol consumption by modulating neurotransmitters believed to be involved in the regulation of alcohol intake.
Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Ibogaína/análogos & derivados , Animales , Relación Dosis-Respuesta a Droga , Ibogaína/farmacología , Masculino , RatasRESUMEN
The purpose of this study was to clarify the effects of iboga agents on cocaine-induced hyperactivity. Both inhibition and enhancement of cocaine-induced activity by ibogaine have been reported. In the present study, rats were treated with either ibogaine (40 mg/kg, i.p.), noribogaine (40 mg/kg, i.p.), 18-methoxycoronaridine (40 mg/kg, i.p.), or saline, 1 or 19 h prior to the administration of cocaine (20 mg/kg, i.p.) or saline. Motor activity was monitored thereafter for 3 h. All three iboga agents had acute inhibitory effects and delayed potentiating effects on cocaine-induced hyperactivity. These time-dependent effects, which could not be attributed to the motor activity induced by the iboga agents alone, account for divergent results reported in the literature.
Asunto(s)
Cocaína/farmacología , Ibogaína/análogos & derivados , Ibogaína/farmacología , Actividad Motora/efectos de los fármacos , Narcóticos/farmacología , Animales , Interacciones Farmacológicas , Femenino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Based on both preclinical findings and anecdotal evidence in man, the psychoactive indole alkaloid ibogaine has been suggested to have anti-addictive properties. Previous studies indicate that blockade of NMDA receptors may mediate at least some of the putative anti-addictive actions of ibogaine. The potencies of a series of ibogaine analogs to inhibit (+)-[3-3H]5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10- imine ([3H]MK-801) binding to NMDA receptors were examined. This series of analogs included the putative ibogaine metabolite O-desmethylibogaine, its metabolism resistant analog O-t-butyl-O-desmethylibogaine, the iboga alkaloids (+/-)-ibogamine, (+/-)-coronaridine, tabernanthine, harmaline, and the indolotropanes endo-3-(1-methylindol-2-yl)-8-methyl-8-azabicyclo[3.2.1]loctane (RS 075194-190), exo-3-(1-methylindol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 075237-190), and endo-3-(indol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 025989-190). Among these compounds, ibogaine was the most potent inhibitor of [3H]MK-801 binding (Ki = approximately 1.2 microM), whilst the compounds with the greatest structural similarity to ibogaine, O-desmethylibogaine and O-t-butyl-O-desmethylibogaine were less potent (Ki = approximately 5.5 and 179.0 microL, respectively). In morphine-dependent mice, ibogaine, but not O-desmethylibogaine or O-t-butyl-O-desmethylibogaine, attenuated naloxone precipitated withdrawal jumping. These findings are consistent with the hypothesis that inhibition of the expression of morphine dependence by ibogaine is related to its NMDA receptor antagonist properties.
Asunto(s)
Ibogaína/análogos & derivados , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Maleato de Dizocilpina/antagonistas & inhibidores , Maleato de Dizocilpina/metabolismo , Cobayas , Ibogaína/metabolismo , Masculino , Ratones , Unión Proteica , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , TritioRESUMEN
Ibogaine, a naturally occurring iboga alkaloid, has been claimed to be effective in treating addiction to opioids and stimulants, and has been reported to inhibit morphine and cocaine self-administration in rats. However, ibogaine also has acute nonspecific side effects (e.g. tremors, decreased motivated behavior in general) as well as neurotoxic effects (Purkinje cell loss) manifested in the vermis of the cerebellum. 18-Methoxycoronaridine (MC) is a novel, synthetic iboga alkaloid congener that mimics ibogaine's effects on drug self-administration without appearing to have ibogaine's other adverse effects. Acutely, in rats, MC decreased morphine and cocaine self-administration but did not affect bar-press responding for water. In some rats, treatment with MC (40 mg/kg) induced prolonged decreases in morphine or cocaine intake lasting several days or weeks. MC had no apparent tremorigenic effect, and there was no evidence of cerebellar toxicity after a high dose (100 mg/kg) of MC. Similar to the effects of ibogaine and other iboga alkaloids that inhibit drug self-administration, MC (40 mg/kg) decreased extracellular levels of dopamine in the nucleus accumbens. MC therefore appears to be a safer, ibogaine-like agent that might be useful in the treatment of addictive disorders.