RESUMEN
The misfolding and fibrillation of human islet amyloid polypeptide (hIAPP) is related to the pathologic process of type II diabetes mellitus (T2DM). The inhibitors of hIAPP aggregation include aromatic organic molecules, short peptides, and metal complexes. Vanadium complexes have been applied for the treatment of diabetes since the 19th century. However, the antidiabetes mechanism remains unclear. In this work, we used four Schiff base oxidovanadium(IV) complexes, namely VO(bhbb)·H2O (1, and ligand 1 H2bhbb, 2-(5-bromo-2-hydroxylbenzylideneamino) benzoic acid), VO(nhbb)·H2O (2, and lignad 2 H2nhbb, 2-(5-nitro-2-hydroxylbenzylideneamino) benzoic acid), VO(cpmp)2 (3, and ligand 3 Hcpmp, 4-chloro-2-(phenylimino) methyl) phenol), and VO(bpmp)2 (4, and ligand 4 Hbpmp, 4-bromo- 2-(phenylmino) methyl) phenol) to inhibit the fibril formation of hIAPP and reduce peptide-induced cytotoxicity. Results indicated that the four Schiff base oxidovanadium complexes effectively impeded hIAPP aggregation and disaggregated mature fibrils into monomers or oligomers. These V complexes also decreased hIAPP-induced cytotoxicity. Among the four V complexes, 1 is a promising candidate metallodrug considering its inhibitory effect, disaggregation ability, regulation of peptide-induced cytotoxicity, and binding affinity to the peptide. Our research provides a new outlook for the design of oxidovanadium complexes as effective inhibitors of hIAPP against T2DM.
Asunto(s)
Antidiarreicos , Polipéptido Amiloide de los Islotes Pancreáticos/antagonistas & inhibidores , Polipéptido Amiloide de los Islotes Pancreáticos/química , Agregado de Proteínas , Vanadatos/química , Antidiarreicos/síntesis química , Antidiarreicos/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Humanos , Bases de Schiff/síntesis química , Bases de Schiff/químicaRESUMEN
The sequential optimization of carboxymethylation of pectin by Plackett-Burman (PB) design and response surface methodology (RSM) was reported in this study. PB design was employed to screen the six process variables (ethanol concentration, liquid-polymer ratio, NaOH concentration, CAA concentration, temperature and time). Central composite design (CCD) was used to study the interaction effects of ethanol concentration, NaOH concentration, CAA concentration and time on degree of substitution (DS) in carboxymethylated pectin (CMP). Maximum DS value of 0.496 was predicted at ethanol concentration (80%), NaOH concentration (38%), CAA concentration (8.5%) and time (60â¯min). The synthesized CMP was characterized by FT-IR, XRD, TGA and viscometer. Results of FTIR, XRD and TGA confirmed the modification made in the pectin polymer and highly methylated. Faster release of 5-FU drug was observed with CMP-chitosan nanoparticles as compared to pectin-chitosan nanoparticles and the drug release followed zero order kinetics model.
Asunto(s)
Antidiarreicos/química , Sistemas de Liberación de Medicamentos , Fluorouracilo/química , Pectinas/química , Antidiarreicos/síntesis química , Metilación , Tamaño de la Partícula , Pectinas/síntesis química , Propiedades de SuperficieRESUMEN
Introduction. Microcos paniculata is traditionally used for treating diarrhea, wounds, cold, fever, hepatitis, dyspepsia, and heat stroke. Objective. To investigate the qualitative phytochemical constituents of hydromethanol (HMPB) and petroleum benzene extract of Microcos paniculata barks (PBMPB) and to evaluate their antinociceptive and antidiarrheal activities. Methods. Phytochemical constituents and antinociceptive and antidiarrheal activities were determined and evaluated by different tests such as Molisch's, Fehling's, Mayer's, Wagner's, Dragendorff's, frothing, FeCl3, alkali, Pew's, and Salkowski's test, general test of glycosides, Baljet and NH4OH test, formalin-induced paw licking, acetic acid-induced writhing, tail immersion, and hot plate tests, and castor oil and MgSO4 induced diarrheal tests. Results. These extracts revealed the presence of saponins, flavonoids, and triterpenoids and significantly (âP < 0.05, versus control) reduced paw licking and abdominal writhing of mice. At 30 min after their administration, PBMPB revealed significant increase in latency (âP < 0.05, versus control) in tail immersion test. In hot plate test, HMPB and PBMPB 200 mg/kg showed significant increase in response latency (âP < 0.05, versus control) at 30 min after their administration. Moreover, both extracts significantly (âP < 0.05, versus control) inhibited percentage of diarrhea in antidiarrheal models. Conclusion. Study results indicate that M. paniculata may provide a source of plant compounds with antinociceptive and antidiarrheal activities.
Asunto(s)
Analgésicos/administración & dosificación , Antidiarreicos/administración & dosificación , Diarrea/tratamiento farmacológico , Metanol/química , Dolor/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Analgésicos/síntesis química , Animales , Antidiarreicos/síntesis química , Benceno/química , Diarrea/diagnóstico , Diarrea/fisiopatología , Evaluación Preclínica de Medicamentos/métodos , Femenino , Masculino , Malvaceae/química , Ratones , Dolor/diagnóstico , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Petróleo , Fitoterapia/métodos , Corteza de la Planta/química , Extractos Vegetales/química , Resultado del Tratamiento , Agua/químicaRESUMEN
Leukemia with a mixed lineage leukemia (MLL) rearrangement, which harbors a variety of MLL fusion proteins, has a poor prognosis despite the latest improved treatment options. Menin has been reported to be a required cofactor for the leukemogenic activity of MLL fusion proteins. Thus, the disruption of the protein-protein interactions between menin and MLL represents a very promising strategy for curing MLL leukemia. Making use of menin-MLL inhibitors with a shape-based scaffold hopping approach, we have discovered that the antidiarrheal loperamide displays previously unreported mild inhibition for the menin-MLL interaction (IC50 = 69 ± 3 µM). In an effort to repurpose this drug, a series of chemical modification analyses was performed, and three of the loperamide-based analogues, DC_YM21, DC_YM25 and DC_YM26 displayed better activities with IC50 values of 0.83 ± 0.13 µM, 0.69 ± 0.07 µM and 0.66 ± 0.05 µM, respectively. Further treatment with DC_YM21 demonstrated potent and selective blockage of proliferation and induction of both cell cycle arrest and differentiation of leukemia cells harboring MLL translocations, which confirmed the specific mechanism of action. In conclusion, molecules of a novel scaffold targeting menin-MLL interactions were reported and they may serve as new potential therapeutic agents for MLL leukemia.
Asunto(s)
Antidiarreicos/farmacología , Loperamida/farmacología , Proteína de la Leucemia Mieloide-Linfoide/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Antidiarreicos/síntesis química , Antidiarreicos/química , Relación Dosis-Respuesta a Droga , Humanos , Loperamida/síntesis química , Loperamida/química , Modelos Moleculares , Estructura Molecular , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Morphiceptin (Tyr-Pro-Phe-Pro-NH(2)), a tetrapeptide present in the enzymatic digest of bovine beta-casein, is a selective ligand of the mu-opioid receptor. In the present study, we describe the synthesis of a series of novel morphiceptin analogs modified in positions 1-3. Two of the obtained analogs, [Dmt(1), D-Ala(2), D-1-Nal(3)]morphiceptin and [Dmt(1), D-NMeAla(2), D-1-Nal(3)]morphiceptin (Dmt-2',6'-dimethyltyrosine and d-1-Nal-3-(1-naphthyl)-D-alanine)) displayed very high mu-receptor affinity, resistance to enzymatic degradation, and remarkable supraspinally mediated analgesia, as shown in the hot-plate test after intracerebroventricular but not intravenous administration, which indicated that they could not cross the blood-brain barrier. Therefore, these two analogs were further tested in vitro and in vivo towards their possible peripheral analgesic activity and inhibitory effect on gastrointestinal (GI) motility. We report that both peptides showed strong antinociceptive effect in the writhing test after intraperitoneal administration, inhibited smooth muscle contractility in vitro and GI motility in vivo. Taken together, these findings indicate that the novel morphiceptin analogs which induce peripheral, but not central antinociception, inhibit GI transit, and possess exceptional metabolic stability, may provide an interesting approach to the development of peripherally restricted agents for the treatment of GI motility disorders, such as diarrhea or diarrhea-predominant irritable bowel syndrome.
Asunto(s)
Endorfinas/química , Endorfinas/síntesis química , Endorfinas/farmacología , Neurotransmisores/síntesis química , Neurotransmisores/farmacología , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Fármacos del Sistema Nervioso Periférico/síntesis química , Fármacos del Sistema Nervioso Periférico/farmacología , Analgésicos Opioides/síntesis química , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Animales , Antidiarreicos/síntesis química , Antidiarreicos/química , Antidiarreicos/metabolismo , Antidiarreicos/farmacología , Colon/efectos de los fármacos , Colon/metabolismo , Diseño de Fármacos , Estabilidad de Medicamentos , Endorfinas/administración & dosificación , Endorfinas/metabolismo , Femenino , Motilidad Gastrointestinal/efectos de los fármacos , Técnicas In Vitro , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Neurotransmisores/química , Neurotransmisores/metabolismo , Oligopéptidos/química , Oligopéptidos/metabolismo , Dimensión del Dolor , Nervios Periféricos/efectos de los fármacos , Fármacos del Sistema Nervioso Periférico/química , Fármacos del Sistema Nervioso Periférico/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Relación Estructura-ActividadAsunto(s)
Meliaceae/química , Alcaloides/síntesis química , Alcaloides/química , Alcaloides/toxicidad , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinfecciosos/toxicidad , Antidiarreicos/síntesis química , Antidiarreicos/química , Antidiarreicos/toxicidad , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/toxicidad , Flavonoides/síntesis química , Flavonoides/química , Flavonoides/toxicidad , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/toxicidad , Terpenos/síntesis química , Terpenos/química , Terpenos/toxicidadRESUMEN
Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.
Asunto(s)
Antidiarreicos/síntesis química , Antidiarreicos/farmacología , Diarrea/tratamiento farmacológico , Loperamida/análogos & derivados , Tiazolidinedionas/síntesis química , Animales , Antidiarreicos/química , Antidiarreicos/uso terapéutico , Aceite de Ricino/toxicidad , Diarrea/inducido químicamente , Loperamida/uso terapéutico , Loperamida/toxicidad , Ratones , Modelos Moleculares , Naloxona/farmacología , Relación Estructura-Actividad , Tiazolidinedionas/químicaRESUMEN
The synthesis by microwave irradiation and the biological results of novel benzotriazinone and saccharine derivatives with potential antidiarrhoeal activity is described. Conventional and microwave heatings were compared for the reactions. Good yields and short reaction times are the main advantages of our synthetic route. Among the tested compounds, compound 12 inhibited motility both in in-vitro and in-vivo tests.
Asunto(s)
Antidiarreicos/síntesis química , Tránsito Gastrointestinal/efectos de los fármacos , Microondas , Sacarina/análogos & derivados , Sacarina/síntesis química , Triazinas/síntesis química , Animales , Antidiarreicos/química , Antidiarreicos/farmacología , Química Farmacéutica , Estimulación Eléctrica , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Sacarina/farmacología , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacologíaRESUMEN
The purpose of this study was to evaluate the potential of polycarbophil-cysteine conjugates (PCP-Cys) as an oral excipient to protect leucine enkephalin (leu-enkp) from enzymatic degradation by the intestinal mucosa. Cysteine was covalently linked to polycarbophil by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC). Inhibitory activity was tested towards isolated aminopeptidase N and excised intact pig intestinal mucosa, with native mucus. Aminopeptidase N activity was assayed spectrophotometrically using L-leucine p-nitroanilide (leu-pNA) as a synthetic substrate and against the model peptide drug leu-enkp, by high-performance liquid chromatography (HPLC). Free cysteine at 6.3 and 63 microM (pH 6) significantly (p < 0.05) inhibited aminopeptidase N activity, and PCP-Cys (0.25% w/v, pH 6) had a significantly (p < 0.05) greater inhibitory effect than PCP on the aminopeptidase N activity towards both substrates. PCP-Cys completely protected leu-enkp against aminopeptidase N activity over a 2-h incubation period, whereas 83 +/- 4 and 60 +/- 7% remained stable in the presence of PCP and buffer only, respectively. Leu-enkp in the absence and presence of PCP (0.25% w/v) at pH 6 was completely digested by the intact intestinal mucosa at the 60- and 90-min incubation time points, respectively, whereas in the presence of PCP-Cys (0.25% w/v, pH 6) 11 +/- 3.5% of leu-enkp remained at the 120-min time point. Thiolation of PCP increased the stability of leu-enkp against the enzymatic degradation by aminopeptidase N and the intact intestinal mucosa, identifying a promising new excipient for peroral delivery of peptides.
Asunto(s)
Resinas Acrílicas/farmacología , Antidiarreicos/farmacología , Antígenos CD13/antagonistas & inhibidores , Mucosa Intestinal/efectos de los fármacos , Reactivos de Sulfhidrilo/metabolismo , Resinas Acrílicas/síntesis química , Animales , Antidiarreicos/síntesis química , Antígenos CD13/metabolismo , Cisteína/síntesis química , Cisteína/metabolismo , Cisteína/farmacología , Mucosa Intestinal/enzimología , Mucosa Intestinal/ultraestructura , Microvellosidades/efectos de los fármacos , Microvellosidades/enzimología , Microvellosidades/ultraestructura , Reactivos de Sulfhidrilo/síntesis química , Reactivos de Sulfhidrilo/farmacología , PorcinosRESUMEN
The syntheses of a group of spermine polyamine analogues and their evaluation as antidiarrheals are described. Each compound was assessed in a rodent castor oil-induced diarrhea model for its ability to reduce stool output and weight loss in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct antidiarrheals. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. The toxicity profile is also quite dependent on these same structural features. On the basis of subcutaneous dose-response data and toxicity profiles, two compounds, N(1),N(12)-diisopropylspermine and N(1),N(12)-diethylspermine, were taken forward into more complete evaluation. These measurements included formal acute and chronic toxicity trials, drug and metabolic tissue distribution studies, and assessment of the impact of these analogues on tissue polyamine pools. Finally, the remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to further explore this framework as a pharmacophore for the construction of other antidiarrheal agents.
Asunto(s)
Antidiarreicos/síntesis química , Ciclohexilaminas/síntesis química , Espermina/análogos & derivados , Espermina/síntesis química , Administración Oral , Animales , Antidiarreicos/química , Antidiarreicos/farmacología , Antidiarreicos/toxicidad , Aceite de Ricino , Ciclohexilaminas/química , Ciclohexilaminas/farmacología , Ciclohexilaminas/toxicidad , Diarrea/inducido químicamente , Diarrea/tratamiento farmacológico , Perros , Femenino , Dosificación Letal Mediana , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratones , Ratas , Ratas Sprague-Dawley , Espermina/química , Espermina/farmacología , Relación Estructura-Actividad , Distribución Tisular , Pruebas de Toxicidad AgudaRESUMEN
A series of aryl-hydroxy-piperidinoalkyl-thiazolidinones was synthesized and evaluated to inhibit castor oil-induced diarrhea in mice. The dose dependent antidiarrheal activity of the most active compound 2-(p-nitrophenyl)-3-¿2-[(4-(p-chlorophenyl)-4-hydroxy)piperidino]ethyl]- 1, 3-thiazolidin-4-one (6) was counteracted by naloxone, resulting comparable with that of loperamide, a mu opiate agonist.
Asunto(s)
Antidiarreicos/farmacología , Piperidinas/farmacología , Tiazoles/farmacología , Animales , Antidiarreicos/síntesis química , Masculino , Ratones , Estructura Molecular , Piperidinas/síntesis química , Tiazoles/síntesis químicaRESUMEN
The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N1,N14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N1,N14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)2-DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)2DEHSPM would have a Ki for polyamine transport essentially identical with that of DEHSPM. The experimentally measured Ki and also the observed values of other biological properties of (HO)2DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)2DEHSPM, and (HO)2DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)2DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.
Asunto(s)
Antidiarreicos/síntesis química , Espermina/análogos & derivados , Animales , Antidiarreicos/química , Antidiarreicos/metabolismo , Antidiarreicos/farmacología , Transporte Biológico , Aceite de Ricino , División Celular/efectos de los fármacos , Simulación por Computador , Diarrea/inducido químicamente , Diarrea/prevención & control , Diseño de Fármacos , Femenino , Riñón/metabolismo , Leucemia L1210 , Hígado/metabolismo , Masculino , Ratones , Modelos Químicos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Espermina/síntesis química , Espermina/química , Espermina/metabolismo , Espermina/farmacología , Células Tumorales CultivadasRESUMEN
Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber with a rabbit ileum preparation. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The 2,6-dimethyl derivative of lofexidine, 4a, was as active as lofexidine in vivo, but derivatives with 2,6-substituents larger than ethyl were inactive. (Aryloxy)alkyl derivatives which have an imidazoline and a methyl or larger group as part of the alkyl exhibited the best antisecretory activity. Compounds with substituents in the para position of the phenyl ring were generally inactive. 3-Amino-2,6-dimethyl derivative 21 was twice as active as 4a. A 2-methyl substituent is required in the 3-amino series to retain good activity. 2-Methyl derivative 12a had activity comparable to that of 4a, while 6-methyl derivative 12f was inactive. Substituents on the 3-amino group did not affect the activity, but substituting a hydroxyl for the amino group produced an inactive compound. Replacing the phenyl moiety with a 4-indole resulted in retention of activity, but other heterocycles were inactive. Compound 12a was resolved and d isomer 32 was five times more potent than l isomer 33. The more active compounds in the rat cholera toxin assay (RCTA), when evaluated in the dog, exhibited antisecretory activity but also exhibited central nervous system (CNS) effects, sedation and ataxia, at 10 mg/kg, and in spontaneously hypertensive rats at 50 mg/kg. A measure of polarity, log P, was calculated for the (aryloxy)alkyl groups. Regression analysis showed no correlation of antisecretory ED50 to the calculated log P. The active compounds did not show a separation of the central CNS effects from the peripheral antisecretory activity by increasing the polarity.
Asunto(s)
Agonistas alfa-Adrenérgicos/síntesis química , Antidiarreicos/síntesis química , Motilidad Gastrointestinal/efectos de los fármacos , Imidazoles/síntesis química , Receptores Adrenérgicos alfa/efectos de los fármacos , Agonistas alfa-Adrenérgicos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Barrera Hematoencefálica , Fenómenos Químicos , Química , Toxina del Cólera/farmacología , Perros , Imidazoles/farmacología , Técnicas In Vitro , Absorción Intestinal/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , TermodinámicaRESUMEN
Guanabenz, a centrally acting antihypertensive agent, has been shown to have intestinal antisecretory properties. A series of aromatic aminoguanidine hydrazones was made in an effort to separate the antisecretory and cardiovascular activities. Benzaldehyde, naphthaldehyde, and tetralone derivatives were synthesized. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber using a rabbit ileum preparation. A number of compounds, including members of each structural class, were active upon subcutaneous administration in the rat. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The compound displaying the best separation of activities was the aminoguanidine hydrazone of 2,6-dimethyl-4-hydroxybenzaldehyde (20).
Asunto(s)
Agonistas alfa-Adrenérgicos/síntesis química , Antidiarreicos/síntesis química , Guanidinas/síntesis química , Hidrazonas/síntesis química , Agonistas alfa-Adrenérgicos/farmacología , Animales , Toxina del Cólera/toxicidad , Femenino , Guanidinas/farmacología , Hidrazonas/farmacología , Íleon/efectos de los fármacos , Íleon/metabolismo , Técnicas In Vitro , Indicadores y Reactivos , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Masculino , Conejos , Ratas , Relación Estructura-ActividadRESUMEN
A series of 4-amino-2,2-diarylbutyronitriles (3) prepared for testing as inhibitors of gastrointestinal propulsive activity did not show any enhancement over such existing agents as diphenoxylate and loperamide. However, conversion of the nitrile group to a 2-methyl-1,3,4-oxadiazol-5-yl function led to compounds 5g and 5j, statistically equipotent to diphenoxylate and loperamide in the mouse and showing a very low order of analgesic activity. Structural modifications determined that the best separation of antipropulsive and analgesic effects was obtained when the amino group was bicyclic and the oxadiazole ring had a 2-methyl substituent. The most potent compounds were and analogues of diphenoxylate and loperamide where the oxadiazole ring was present, but these compounds had marked analgesic activity.