RESUMEN
We developed a dye-binding method for albumin in urine based on bis (3',3"-diiodo4'4"-dihydroxy-5'5"-dinitrophenyl)-3,4,5,6-tetrabr omosulfonphthalein (DIDNTB), a dye that has a higher chemical sensitivity and specificity for albumin when compared to two other commonly used dyes. We prepared urine dipsticks with DIDNTB and certain other compounds to prevent "nonspecific" binding to the dipstick matrix. The detection limit for albumin with DIDNTB as the dye is about 10 mg/L. The extent of dye binding to proteins and other compounds was studied using ultracentrifugation and a selectively permeable membrane that permitted the passage of free but not bound dye; we believe this method is superior to photometric titration. The affinity of the dyes for albumin was found to be pH dependent with stronger binding at pH 1.8 than at pH 7.0. At pH 1.8, DIDNTB had a ca.10-fold greater binding coefficient to albumin when compared to the widely used dyes, tetrabromophenol blue (CI 4430-25-5) or bromophenol blue (CI 115-39-9). We developed a system that minimized nonspecific binding by the dye through the use of polymethyl vinyl ethers and bis-(heptapropylene glycol) carbonate. DIDNTB showed a greater chemical specificity for albumin when compared to most other proteins. The new albumin dipsticks are resistant to many potential interferences at substantial concentrations, making the dipsticks suitable to screen for albuminuria.
Asunto(s)
Colorantes , Fenolsulfonftaleína/análogos & derivados , Albúmina Sérica/análisis , Azul de Bromofenol/química , Colorantes/química , Humanos , Inmunoglobulinas/química , Inmunoglobulinas/orina , Fenolsulfonftaleína/química , Unión Proteica , Sensibilidad y Especificidad , Albúmina Sérica/química , Urinálisis/métodosRESUMEN
A series of [(6,7-dichlorobenzo[b]thien-5-yl)oxy]acetic acids and their corresponding 1,1-dioxides were synthesized and evaluated for diuretic activity in the acute saline loaded mice (ASLM) and hypotensive activity in the spontaneously hypertensive rat (SHR). A significant number of compounds were found to display potent activity in one or both assays, and preliminary structure-activity relationships with respect to each assay were delineated. Compound 94, the 1,1-dioxide of [(6,7-dichloro-2-n-propylbenzo[b]thien-5-yl)oxy]acetic acid was markedly active in both the ASLM and SHR by oral administration. The combined diuretic/hypotensive profile of this compound was further substantiated by its good saluretic response in water loaded conscious dogs and a moderate to good activity in renal hypertensive rats and sinoaortic-deafferented hypertensive dogs.
Asunto(s)
Antihipertensivos/síntesis química , Diuréticos/síntesis química , Glicolatos/síntesis química , Tiofenos/síntesis química , Acetatos/síntesis química , Acetatos/farmacología , Animales , Antihipertensivos/farmacología , Diuréticos/farmacología , Perros , Femenino , Glicolatos/farmacología , Masculino , Ratones , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas , Relación Estructura-Actividad , Tiofenos/farmacologíaRESUMEN
A series of 1-arylspiro[indoline-3,4'-piperidine]s was synthesized and evaluated for potential antidepressant activity by tetrabenazine (TBZ) ptosis prevention and potentiation of 5-hydroxytryptophan (5-HTP) induced head twitching in pargyline-pretreated rats. Marked TBZ activity was observed with analogues bearing an ortho substituent on the pendant aromatic ring, as exemplified by lead compound 25a, 1-(2-chlorophenyl)spiro[indoline-3,4'-piperidine], which was also very active in potentiating 5-HTP stereotypy and yohimbine toxicity, as well as in inhibiting the muricidal behavior in rats. The potent in vivo activity of 25a, coupled with weak to moderate in vitro activity with respect to the blockade of neuronal reuptake of biogenic amines, seems to suggest a profile atypical of tricyclic antidepressants.
Asunto(s)
Antidepresivos/síntesis química , Indoles/síntesis química , Piperidinas/síntesis química , 5-Hidroxitriptófano/farmacología , Animales , Bioensayo , Blefaroptosis/fisiopatología , Sinergismo Farmacológico , Humanos , Indicadores y Reactivos , Indoles/farmacología , Piperidinas/farmacología , Conducta Estereotipada/efectos de los fármacos , Relación Estructura-Actividad , Tetrabenazina/toxicidadRESUMEN
A series of [[(alkylamino)ethyl]thio]dibenz[b,f]thiepins (III) and their 10,11-dihydro derivatives (IV) was synthesized and subjected to broad analgesic/CNS screening. Preliminary results indicated a combination of analgesic/antidepressant profiles, similar to that observed for the [[(alkylamino)ethyl]thio]dibenz[b,f]oxepins (I) and their corresponding dihydro derivatives (II). The most active congener from the present series, 10b, shows an antinociceptive potency in the pentazocine range as assessed by phenyl-p-quinone-induced writhing (PQW) and tail flick in mice. It is also more than twice as active as imipramine in preventing tetrabenazine-induced ptosis (TBZ), a test widely recognized to be of predictive value for clinically efficacious antidepressants.
Asunto(s)
Analgésicos/síntesis química , Antidepresivos Tricíclicos/síntesis química , Benzoquinonas , Dibenzotiepinas/síntesis química , 5-Hidroxitriptófano/antagonistas & inhibidores , Anfetamina/antagonistas & inhibidores , Animales , Antipsicóticos/síntesis química , Apomorfina/antagonistas & inhibidores , Blefaroptosis/prevención & control , Fenómenos Químicos , Química , Dibenzotiepinas/farmacología , Humanos , Masculino , Quinonas/antagonistas & inhibidores , Ratas , Conducta Estereotipada/efectos de los fármacosRESUMEN
The Prostatic-Group-Label Immunoassay (PGLIA) technique has been incorporated into a reagent-strip format. We report use of flavin N6-(N'-2,4-dinitrophenyl-6-aminohexyl)adenine dinucleotide (DNP-FAD) as the prosthetic group derivative and 6-N-(2,4-dinitrophenyl)aminohexanoic acid (DNP-caproate) as the competing ligand. DNP-FAD not bound by antibody combines with glucose oxidase apoenzyme, which then reacts with glucose and oxygen, and gives color through a peroxidase-linked system. The rate of color generation is thus a function of the DNP-caproate concentration. PGLIA reagent strips are prepared by sequential impregnations of filter paper with an acetone solution of indicator (3,3',5,5'-tetramethylbenzidine); an aqueous solution containing glucose oxidase apoenzyme, the rest of the color generation system, stabilizers, and antibody to DNP; and a solution of DNP-FAD in n-propanol. This preparation permits effective antibody binding, and prevents premature interaction of immunoassay components. A quantitative color response to concentrations of DNP-caproate in the range of 1 to 8 mumol/L was demonstrated with these reagent strips. Prototype PGLIA reagent strips for theophylline and phenytoin have been successfully developed by substituting the appropriate FAD derivative and antibody for the corresponding reagents in the DNP model system.
Asunto(s)
Inmunoensayo/métodos , Indicadores y Reactivos , Tiras Reactivas , Aminocaproatos , Apoenzimas , Unión Competitiva , Flavina-Adenina Dinucleótido/análogos & derivados , Flavina-Adenina Dinucleótido/síntesis química , Glucosa Oxidasa , Ligandos , Fenitoína/análisis , Teofilina/análisisRESUMEN
A series of 3-aryl-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidine] derivatives was synthesized and evaluated pharmacologically for potential psychotropic activity. Potent antidepressant-like activity was noted throughout the series, as assessed by tetrabenazine (TBZ) ptosis prevention in mice and potentiation of 5-hydroxytryptophan (5-HTP) induced behavioral effects in rats. A possible therapeutic advantage of the title compounds appears to be the overall low anticholinergic potential in comparison with the classic tricyclic antidepressants. Several congeners with nuclear halogen substitution also exhibited CNS stimulant properties, as evidenced by their ability to induce a dopamine agonist-like stereotypy and to increase the spontaneous motor activity in mice.
Asunto(s)
Antidepresivos Tricíclicos/síntesis química , Piperidinas/síntesis química , Compuestos de Espiro/síntesis química , 5-Hidroxitriptófano/farmacología , Animales , Blefaroptosis/inducido químicamente , Fenómenos Químicos , Química , Sinergismo Farmacológico , Masculino , Ratones , Fisostigmina/farmacología , Piperidinas/farmacología , Compuestos de Espiro/farmacología , Tetrabenazina/antagonistas & inhibidoresRESUMEN
A series of [[(alkylamino)ethyl]thio]dibenz[b,f]oxepins (I) and their 10,11-dihydro derivatives (II) was synthesized and subjected to broad analgesic/CNS screening. Several analogues of both types, carrying small N-substituents and frequently a nuclear fluorine function, have been found to possess potent analgesic activity in the phenylquinone writhing assay (PQW) and the tail-flick test in mice. Many of these compounds also exhibited significant activity in antagonizing tetrabenazine-induced ptosis, as exemplified by 10b, 16b, and 18b. Results from the mouse jumping test indicated low physical dependence potential for these compounds, and further evidence for a nonnarcotic profile was provided by the absence of significant naloxone interactions with the tail-flick response. Compound 10b did not produce tolerance in mice following chronic administration in the PQW screen.
Asunto(s)
Analgésicos/síntesis química , Antidepresivos Tricíclicos/síntesis química , Dibenzoxepinas/síntesis química , Anfetamina/antagonistas & inhibidores , Anfetamina/toxicidad , Animales , Anticonvulsivantes , Antipsicóticos , Fenómenos Químicos , Química , Dibenzoxepinas/farmacología , RatonesRESUMEN
A series of 10,11-dihydro-11-oxospiro[dibenz[b,f]oxepin-10,4'-piperdine] derivatives (II) was synthesized and evaluated for analgesic activity in the phenylquinone writhing assay (PQW) and the tail-flick test in mice. Preliminary structure-activity correlations indicate that optimum activity is associated with a short-chain (R less than or equal to C2) N substituent and a nuclear fluorine function, as exemplified by 9b. This compound, when administered orally, was equipotent to morphine in protecting against mouse writhing. The observation that the PQW activity of 9b remained relatively unchanged after naloxone challenge seems to favor a nonnarcotic profile.