RESUMEN

The development of a synthetic approach to the novel pyrrolo[2, 1-b][1,3]benzothiazepine and its derivatives and their biological evaluation as potential antipsychotic drugs are described. In binding studies these compounds proved to be potent 5-HT2, D2, and D3 receptor ligands. The more potent benzothiazepine (+/-)-3b was resolved into its enantiomers by using HPLC techniques. In vitro testing confirmed that (-)-3b is a more potent D2 receptor ligand, maintaining high affinity for 5-HT2 receptors. In contrast, the (+)-3b enantiomer presents a 35 times higher affinity for 5-HT2 than for dopamine D2 receptors with a similar dopamine D1 receptor affinity to that of (-)-3b. Overall, (+)-3b shows an "atypical" neuroleptic binding profile, while (-)-3b has a more "classical" profile. Furthermore pharmacological and biochemical testing displayed that the novel benzothiazepine (+/-)-3b is able to increase the extracellular levels of dopamine in the rat striatum and causes a dose-related suppression of apomorphine-induced locomotor activity. At low doses (+/-)-3b does not induce catalepsy, showing atypical antipsychotic properties similar to those of olanzapine. These heterocyclic compouds represent new leads for the development of novel antipsychotic drugs with atypical properties.

Asunto(s)

Antipsicóticos/síntesis química , Antagonistas de Dopamina/síntesis química , Pirroles/síntesis química , Antagonistas de la Serotonina/síntesis química , Tiazepinas/síntesis química , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Antipsicóticos/química , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Catalepsia/inducido químicamente , Dopamina/metabolismo , Antagonistas de Dopamina/química , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Actividad Motora/efectos de los fármacos , Pirroles/química , Pirroles/metabolismo , Pirroles/farmacología , Ratas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Tiazepinas/química , Tiazepinas/metabolismo , Tiazepinas/farmacología

RESUMEN

A series of 2-aminotetralins, substituted with a methoxy or a hydroxy group on the 5- or 7-position, and with varying N-alkyl or N-arylalkyl substituents, were prepared and evaluated in binding assays for human dopamine (DA) D2, D3, and D4 receptors. Some members of this series were prepared in former studies, but were never tested in vitro with single receptor subtypes, and these were examined again. None of the tested 2-aminotetralins showed high affinity for the dopamine D4 receptor. However, a number of the 2-aminotetralins showed high affinity for both the D2 and the D3 DA receptors, as exemplified by compounds 11-15 and 21-26, while some had a reasonable selectivity for the DA D3 receptors. The affinities of the 2-aminotetralins for the D21, receptor depended on the type of radioligand (agonist or antagonist) used. The agonist affinity data, obtained by using the agonist ligand [3H]N-0437, are thought to be more relevant for calculating DA receptor subtype selectivity.

Asunto(s)

Receptores de Dopamina D2/metabolismo , Tetrahidronaftalenos/metabolismo , Animales , Línea Celular , Cricetinae , Cricetulus , Femenino , Humanos , Cinética , Ovario/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3 , Receptores de Dopamina D4 , Especificidad por Sustrato , Tetrahidronaftalenos/química

RESUMEN

The affinity and intrinsic activity of dopamine receptor agonists were determined at the human dopamine hD21 and hD4.4 receptors. (-)-3-Hydroxy-N-n-propylpiperidine ((-)3-PPP) had an intrinsic activity of 46% and 83%, whereas (+)-N-propylnorapomorphine ((+)-NPA) had intrinsic activities of 61% and 58% at the dopamine hD21 and hD4.4 receptors, respectively. Affinities also varied. A single, or multiple, dopamine D2-type receptor(s) may be involved in schizophrenia and agonists are being tested as therapy. Understanding their properties at the individual dopamine D2-family receptors is important.

Asunto(s)

Agonistas de Dopamina/farmacología , Agonistas de Dopamina/farmacocinética , Receptores de Dopamina D2/agonistas , Aminoquinolinas/farmacología , Animales , Células CHO , Membrana Celular/metabolismo , Cricetinae , Antagonistas de Dopamina/farmacología , Humanos , Piperidinas/farmacología , Racloprida , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Salicilamidas/farmacología

RESUMEN

We addressed the role of thiamin, a cofactor for several enzymes involved in glucose metabolism, in the glucose metabolic response to endotoxin. Characterized by hyperglycemia, increased hepatic glucose production exceeding elevated rates of whole-body glucose utilization, this response is mediated by hormones and cytokines and is dependent on the immune and nutritional status of the host. We hypothesized that a thiamin-deficient state would impair the metabolic response to endotoxin. Rats were fed a thiamin-deficient or control diet for 6 wk before in vivo assessment of glucose kinetics. In control rats, Escherichia coli endotoxin increased the rate of glucose appearance (+76%), disappearance (+70%), and metabolic clearance (+50%). Thiamin deficiency resulted in increased plasma glucose (18%) and lactate (3- to 4-fold) as well as in a 30% decrease in insulin and an increase in glucagon (2.6-fold) and corticosterone (3.6-fold). Thiamin deficiency inhibited the endotoxin-induced hyperglycemia and the rise in hepatic glucose production, glucose utilization, and metabolic clearance rate.

Asunto(s)

Endotoxinas/farmacología , Glucosa/metabolismo , Hígado/metabolismo , Deficiencia de Tiamina/metabolismo , Animales , Glucemia/análisis , Ingestión de Energía , Escherichia coli , Privación de Alimentos , Insulina/sangre , Glucógeno Hepático/metabolismo , Masculino , Tasa de Depuración Metabólica , Ratas , Ratas Sprague-Dawley

RESUMEN

The effects of a thiamine-deficient diet on plasma and tissue vitamin concentrations and on whole-body glucose metabolism were assessed. Male Sprague-Dawley rats (175 to 200 g body weight) fed a thiamine-deficient (TD) or nutritionally complete purified diet were used for plasma thiamine mononitrate and monophosphate and for red blood cell and tissue thiamine pyrophosphate (TPP) determinations weekly for up to 5 weeks. Additional rats were used for assessment of basal glucose kinetics by using a primed constant infusion of [3-3H]glucose. Plasma thiamine mononitrate levels decreased 60% at 1 week and were undetectable after 5 weeks on the diet. Plasma thiamine monophosphate decreased 80% after 1 week on the TD diet, and levels were undetectable after 4 weeks on the diet. Red blood cell TPP in the TD group decreased progressively with time: 54% at 1 week, 86% at 3 weeks, and 92% at 5 weeks. At 1 and 4 weeks, the decrease in tissue TPP was significant in the liver (65% and 89%, respectively), gut (52% and 94%, respectively), spleen (40% and 60%, respectively), and skeletal muscle (37% and 76%, respectively), with the brain (7% and 84%, respectively) showing the slowest initial rate of depletion. The TD diet did not alter plasma glucose concentrations, but it increased plasma lactate by 75% and plasma pyruvate by 50% to 75%. Rates of hepatic glucose production and peripheral glucose utilization were not different between the control and TD rats at 2 weeks, but they were 25% higher in the TD rats after 6 weeks on the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Glucosa/metabolismo , Deficiencia de Tiamina/metabolismo , Animales , Peso Corporal , Dieta , Modelos Animales de Enfermedad , Ingestión de Energía , Privación de Alimentos , Cinética , Masculino , Ratas , Ratas Sprague-Dawley , Tiamina/análisis , Tiamina/sangre , Deficiencia de Tiamina/sangre

RESUMEN

The metabolism of the dopamine D2 agonist N-0923 was investigated by an in vitro isolated liver perfusion. Determining the metabolic profile and identity of the different metabolites was achieved by using high-performance liquid chromatography with UV detection, combined with atmospheric pressure ionization mass spectrometry. Using this technique, no extensive sample cleanup is required, and the studies can be performed without radioactivity. In addition to previously observed metabolites, nine new metabolic products were identified. All metabolites were exclusively excreted into the bile, except for the despropyl metabolite, which was also detectable in the perfusate. 5-O-Glucuronidation and N-depropylation followed by 5-O-glucuronidation are the most important metabolic routes. N-dealkylation of the thienylethyl group followed by 5-O-glucuronidation and sulfation is a second major metabolic pathway. Catechol formation of the despropyl metabolite with or without subsequent conjugation was not found. Catechol formation of the desthienylethyl metabolite occurred, but only its glucuronide conjugates were found. This study complements previous results of in vivo metabolic studies using the radiolabeled racemate N-0437, and it explains differences in bile excretion during isolated liver perfusions using N-0923 and radiolabeled N-0923.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Dopaminérgicos/análisis , Hígado/química , Espectrometría de Masas/métodos , Tetrahidronaftalenos/análisis , Tiofenos/análisis , Animales , Bilis/química , Dopaminérgicos/metabolismo , Técnicas In Vitro , Masculino , Perfusión , Ratas , Ratas Wistar , Espectrofotometría Ultravioleta , Tetrahidronaftalenos/metabolismo , Tiofenos/metabolismo

RESUMEN

The aim of the present study was to elucidate the effect of kainate and N-methyl-D-aspartate (NMDA), two different excitatory amino acid (EAA) agonists, on glucoregulatory hormone production and whole body glucose metabolism. Rates of hepatic glucose production (HGP) and peripheral glucose utilization (GU) were assessed in overnight fasted, catheterized, conscious rats using [3-3H]glucose. At the highest dose of kainate examined (16 mg/kg), glucose levels increased 97% after 1 h; thereafter, glucose fell towards basal values but was still elevated 25% at the end of the 3 h experiment. This hyperglycemia resulted from a rapid increase in HGP that exceeded an increased rate of GU. Both HGP and GU were elevated 86% throughout the final 2 h of the experiment. NMDA induced changes in glucose flux that were qualitatively similar, yet of smaller magnitude and of shorter duration, than those produced by kainate. Kainate-induced increases in glucose metabolism were associated with an early transient hyperinsulinemia followed by a period of insulinopenia, and sustained increases in the plasma concentrations of glucagon, corticosterone, epinephrine and norepinephrine. In contrast, sustained increases in glucagon and catecholamines, as well as the late hypoinsulinemia were not detected in NMDA-treated rats. Adrenergic blockade attenuated the kainate- but not the NMDA-induced increase in glucose metabolism. These results indicate that EAA agonists that bind preferentially to different receptor subtypes produce qualitatively similar changes in glucose metabolism. Whereas the increased HGP in kainate-injected rats was associated with sustained elevations in glucagon, catecholamines and corticosterone, NMDA only transiently elevated circulating glucocorticoid levels, suggesting a different mechanism of action. These data, support the involvement of EAA in various aspects of glucoregulation.

Asunto(s)

Corticosterona/metabolismo , Glucagón/metabolismo , Glucosa/metabolismo , Insulina/metabolismo , Ácido Kaínico/farmacología , N-Metilaspartato/farmacología , Antagonistas Adrenérgicos , Animales , Presión Sanguínea/efectos de los fármacos , Glucógeno/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Secreción de Insulina , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Aminoácidos/metabolismo , Estrés Fisiológico/fisiopatología

RESUMEN

One of the hallmarks of the stress response is an increased rate of hepatic glucose production (HGP) which, in conjunction with the presence of insulin resistance, leads to hyperglycemia. Excitatory amino acids (EAA) within the brain mediate some of the cardiovascular responses to stress, but their role in the hormonal and metabolic alterations is poorly defined. The aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of either N-methyl-D-aspartate (NMDA) or kainate would produce metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. After an overnight fast, HGP and peripheral glucose utilization (GU) were assessed in conscious unrestrained rats using [3-3H]glucose. Arterial glucose levels were increased 34% by 15 min after the i.c.v. injection of NMDA (1 microgram) and remained elevated throughout the 3-h protocol. The hyperglycemia resulted from an early increase in HGP (84%) that exceeded a smaller elevation (66%) in GU. The increased glucose flux was associated with sustained insulinopenia (-30%), and elevated levels of corticosterone (40-100%) and epinephrine (75-216%). The hormonal and glucose metabolic responses were quantitatively similar, although of shorter duration, in rats injected with kainate (10 ng). Intravenous adrenergic blockade completely prevented the NMDA-induced hyperglycemia. Adrenergic blockade blunted the early rise in HGP, so that in this group the NMDA-induced increase in HGP was offset by a comparable elevation in GU.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Glucosa/metabolismo , Hormonas/sangre , Hígado/efectos de los fármacos , N-Metilaspartato/administración & dosificación , Norepinefrina/fisiología , Estrés Fisiológico/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intraventriculares , Insulina , Ácido Kaínico/farmacología , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico/sangre

RESUMEN

The R-(+)-isomer of 7-hydroxy-2-(N,N-di-n-propylamino)tetralin (7-OH-DPAT) bound with a more than 200-fold higher affinity to cloned human dopamine D3 receptors (Ki = 0.57 nM) than to dopamine D2 receptors; the corresponding S-(-)-enantiomer had considerably less affinity for both dopamine receptor subtypes, indicating that the known enantiomer selectivity of 7-OH-DPAT for the 'classical' dopamine D2 receptor subtype extends to the recently discovered dopamine D3 receptor subtype. In rats R-(+)-7-OH-DPAT dose dependently (10-1000 nmol/kg) decreased dopamine release and induced yawning, while sniffing behaviour occurred at the highest dose tested (1000 nmol/kg). The possibility that the inhibition of dopamine release and the elicitation of yawning are mediated by dopamine D3 receptors is considered.

Asunto(s)

Conducta Animal/efectos de los fármacos , Receptores de Dopamina D2 , Receptores Dopaminérgicos/metabolismo , Tetrahidronaftalenos/farmacología , Animales , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Wistar , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Dopamina D3 , Estereoisomerismo , Tetrahidronaftalenos/metabolismo , Bostezo/efectos de los fármacos

RESUMEN

A series of unsubstituted and methoxy-substituted 2-amidotetralins (4a-q) was prepared and evaluated for their ability to compete for 2-[125I]iodomelatonin binding to chicken retinal membranes and for their potency to inhibit the calcium-dependent release of [3H]dopamine from rabbit retina. The lead compound, 2-acetamido-8-methoxytetralin (4j), showed a moderate affinity (Ki = 46 nM) and potency (IC50 = 1.4 nM) at the melatonin receptor. The structural requirements necessary for optimal agonistic activity at the melatonin receptor are as follows. First, the amido group, which should have a small, nonbranched alkyl group, is essential for affinity, and second, the methoxy substituent at the 8-position of the 2-amidotetralin ring is essential for optimal agonistic activity at the melatonin receptor. We concluded that this series of unsubstituted and methoxy-substituted 2-amidotetralins constitutes a class of nonindolic melatonin-like agents that can be used as pharmacological tools to further characterize melatonin receptors and to elucidate the mode of action of melatonin.

Asunto(s)

Melatonina/farmacología , Receptores de Superficie Celular/efectos de los fármacos , Tetrahidronaftalenos/síntesis química , Animales , Unión Competitiva , Calcio/farmacología , Membrana Celular/metabolismo , Pollos , Dopamina/metabolismo , Radioisótopos de Yodo , Melatonina/metabolismo , Conejos , Receptores de Superficie Celular/metabolismo , Receptores de Melatonina , Retina/metabolismo , Relación Estructura-Actividad , Tetrahidronaftalenos/metabolismo , Tetrahidronaftalenos/farmacología

RESUMEN

Hyperglycemia is a hallmark of the stress response, and has been largely attributed to elevated plasma levels of catabolic hormones. Recently, various cytokines have been shown to be endogenously produced within the brain and may represent an important component of the central regulation of this metabolic response. Therefore, the aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of one such peptide, interleukin (IL)-1, can produce hormonal and metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. Whole body glucose flux was assessed in overnight fasted conscious unrestrained rats using [3-3H]glucose. A mild hyperglycemia was elicited 20 min after the i.c.v. injection of IL-1 alpha (human recombinant, 100 ng) that was not detected in control rats. Glucose levels gradually increased and were 26% higher than control values during the last hour of the 3 h experimental period. The hyperglycemia resulted from a 44% increase in the rate of hepatic glucose output (HGO), which preceded a proportional rise in peripheral glucose utilization. No increase in metabolic clearance rate was observed, suggesting that the increased glucose uptake was the result of mass action. The increased glucose flux was associated with a transient hyperinsulinemia (+95%), and sustained elevations in the arterial concentrations of glucagon (56%) and corticosterone (175%). In contrast, glucose flux was not altered by intravenous administration of the same dose of IL-1 alpha, or i.c.v. injection of IL-1 beta, or heat-inactivated IL-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Adyuvantes Inmunológicos/fisiología , Sistema Nervioso Central/fisiología , Glucosa/metabolismo , Interleucina-1/fisiología , Animales , Dinoprostona/farmacología , Relación Dosis-Respuesta a Droga , Hormonas/sangre , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes

RESUMEN

The enantiomers of a series of dopamine (DA) agonists, monohydroxy-2-aminotetralin derivatives, were investigated using brain microdialysis. We used a 5-OH-substituted derivative, N-0437 (2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin), and three 7-OH-substituted derivatives, N-0438 (2-(N-propyl-N-2-thienylethylamino)-7-hydroxytetralin), 7-OH-DPAT (7-hydroxy-2-(N,N-di-n-propylamino)tetralin) and PHNO (4-propyl-9-hydroxynaphthoxazine; position 9 of the naphtoxazines corresponds to position 7 of the aminotetralins). We studied the activity of the enantiomers at autoreceptors regulating the release of DA following their local infusion into the striatum of the rat. We were particularly interested in the activity of R(+)-N-0437, S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, which are enantiomers that have been classified as less potent or inactive in previous studies. S(-)-N-0437, R(+)-N-0438, R(+)-7-OH-DPAT and R(+)-PHNO decreased DA release by 45-60%. Thus, these enantiomers are potent agonists at autoreceptors regulating the release of DA. The R(+) enantiomer of the 5-OH-substituted derivative N-0437 possessed antagonistic activity at autoreceptors controlling DA release, increasing DA release by 100%. This finding is consistent with reports showing that one enantiomer of other 5-OH DA agonists displays agonistic activity, while the other has antagonistic properties at DA autoreceptors. The less potent enantiomers of the 7-OH-substituted derivatives S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, however, all showed weak agonistic activity at DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Cuerpo Estriado/metabolismo , Dopaminérgicos/farmacología , Dopamina/metabolismo , Receptores Dopaminérgicos/efectos de los fármacos , Animales , Cromatografía Líquida de Alta Presión , Cuerpo Estriado/efectos de los fármacos , Diálisis , Masculino , Oxazinas/metabolismo , Oxazinas/farmacología , Ratas , Ratas Endogámicas , Receptores Dopaminérgicos/metabolismo , Estadística como Asunto , Estereoisomerismo , Tetrahidronaftalenos/metabolismo , Tetrahidronaftalenos/farmacología , Tiofenos/metabolismo , Tiofenos/farmacología

RESUMEN

Derivatives of the potent dopamine D2-selective agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) were designed, aimed at producing drugs with less sensitivity towards metabolic inactivation (in particular glucuronidation at the 5-OH position). Since aminotetralins with a 5-methoxy substituent or lacking the 5-hydroxy group have been reported to retain dopaminergic activity, the non-5-hydroxylated N-0437 (N-0918) and two ethers of N-0437 [5-methoxy-N-0437 (N-0724) and 5-cyclopentoxy-N-0437 (N-0953)] have been prepared and tested. Three indices for activity at central dopamine receptors are considered: (1) the displacement of (3H)-SCH-23390 and (3H)-spiperone from calf caudate membranes, (2) the effects on dopamine release and metabolism in the striatum of freely moving rats after systemic and intrastriatal administration as assessed by brain microdialysis, and (3) the ability to elicit contralateral turning in rats with a unilateral 6-OH-dopamine lesion of the nigrostriatal pathway. In order to differentiate between direct dopaminergic activity and metabolic activation, brain and plasma levels of N-0437 after administration of N-0724 and N-0953 were measured. The results show the necessity of the 5-OH group for direct dopaminergic activity: N-0918, N-0724 and N-0953 are all inactive after intrastriatal administration in the microdialysis model and all three drugs show a weak in vitro affinity for both D1 and D2 receptors. Although N-0918 is also inactive after systemic administration in the microdialysis and turning model, N-0724 and N-0953 do exhibit dopaminergic activity after systemic administration in these models.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Dopaminérgicos/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Tetrahidronaftalenos/farmacología , Tiofenos/farmacología , Animales , Encéfalo/efectos de los fármacos , Diálisis , Éteres/farmacología , Hidroxidopaminas/farmacología , Hidroxilación , Masculino , Modelos Biológicos , Estructura Molecular , Actividad Motora/efectos de los fármacos , Oxidopamina , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas , Receptores de Dopamina D2 , Rotación

RESUMEN

The in-vivo activities of eight carbamate prodrugs of the D2-agonist N-0437 were determined by examining the effects of the prodrugs, after their oral administration in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used as an index of the activity of the compounds. A comparison of the area under the curve of the time-effect curves of the prodrugs, revealed a significantly improved duration of action compared with N-0437 during the period 11-15 h after administration, for the propylcarbamate and the dimethoxyphenylcarbamate derivatives. The 2,4-dimethylphenylcarbamate showed a significantly enhanced turning behaviour over the whole 15 h time interval in comparison with N-0437. Three of the nine carbamates were virtually unhydrolysed in rat serum at 37 degrees C, while the other test compounds were hydrolysed relatively slowly, with t1/2 values ranging from 1.5-6 h. The test compounds differed greatly in partition coefficients, which were estimated by RP-HPLC (1-12 times more lipophilic than N-0437). The potential cholinesterase inhibiting properties of the carbamate prodrugs were assessed by a simple in-vitro incubation assay, which showed that only two carbamates were very weak cholinesterase inhibitors.

Asunto(s)

Conducta Animal/efectos de los fármacos , Carbamatos/farmacocinética , Dopaminérgicos/farmacocinética , Hidroxidopaminas/farmacología , Profármacos/farmacocinética , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Administración Oral , Animales , Carbamatos/metabolismo , Carbamatos/farmacología , Inhibidores de la Colinesterasa/farmacología , Cromatografía Líquida de Alta Presión , Dopaminérgicos/metabolismo , Dopaminérgicos/farmacología , Hidrólisis/efectos de los fármacos , Hidroxidopaminas/antagonistas & inhibidores , Masculino , Oxidopamina , Profármacos/metabolismo , Profármacos/farmacología , Ratas , Ratas Endogámicas , Tetrahidronaftalenos/metabolismo , Tetrahidronaftalenos/farmacología , Tiofenos/metabolismo , Tiofenos/farmacología

RESUMEN

The potent and selective D2-agonist N-0437 [2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin] undergoes considerable first-pass metabolism after oral administration due to glucuronidation of the phenolic group. In an attempt to improve its bioavailability, seven ester prodrugs of N-0437 were synthesized, i.e. the acetyl-, propionyl-, isobutyryl-, pivaloyl-, 2-amino-phenyl-, 2-methoxy-phenyl- and 2,4-dimethylphenyl-analogues. In vivo activities were assessed by measuring contralateral turning after transdermal administration of N-0437 and its prodrugs to rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. From time-effect curves the area under the curve for separate time intervals was taken as a measure of dopaminergic activity during that interval. It was found that slowly hydrolyzing prodrugs, which are known to show an improved duration of action after oral administration, are devoid of activity after transdermal application. The acetyl-, the propionyl- and the isobutyryl analogues, which are prodrugs with a relatively high hydrolysis rate, were found to have interesting and promising profiles following transdermal application.

Asunto(s)

Dopaminérgicos/farmacología , Dopamina/fisiología , Hidroxidopaminas/metabolismo , Profármacos/farmacología , Tetrahidronaftalenos/farmacología , Tiofenos/farmacología , Administración Cutánea , Administración Oral , Animales , Dopaminérgicos/administración & dosificación , Masculino , Oxidopamina , Profármacos/administración & dosificación , Ratas , Ratas Endogámicas , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Tetrahidronaftalenos/administración & dosificación , Tiofenos/administración & dosificación

RESUMEN

The metabolism of 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) was investigated in conscious monkeys after subsequent i.v., oral, and ocular administration. The administration of the drug caused some physiological effects, such as bradycardia and sedation of the monkeys. During a collection period of 120 hr, on average 83% was recovered after iv administration and 90% after p.o. dosing. After i.v. administration, 44% was excreted in the bile, as compared to 38% in the urine and about 1% in the feces. After oral administration, bile is the major excretion route, accounting for about 60% of the dose, as compared to 25% in the urine and about 5% in the feces. After ocular administration, on average 62% was recovered after 7 hr, excreted in bile and urine in about equal amounts. All percentages given above reflect the total amount of radioactivity recovered, thus comprising the unchanged drug plus various metabolites. After all three dosing routes, N-0437 was metabolized almost completely prior to elimination. Direct glucuronidation of the phenolic group proved to be the major metabolic pathway of N-0437, comprising about 44% of the dose after i.v. and ocular administration and 72% after oral dosing. Hydroxylation of N-0437 at the position ortho to the phenolic group present yielded a catechol intermediate, which was excreted as a glucuronide and accounted for about 10% of the dose. In the monkey, a clear regioselective preference towards glucuronidation at the 6-position was observed. Besides the glucuronide, the sulfoconjugate of N-0437 was a major metabolite after i.v. and ocular administration, accounting for about 15% of the dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Dopaminérgicos/metabolismo , Tetrahidronaftalenos/metabolismo , Tiofenos/metabolismo , Administración Oral , Animales , Bilis/metabolismo , Biotransformación , Dopaminérgicos/farmacocinética , Heces/química , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intravenosas , Macaca , Masculino , Soluciones Oftálmicas , Espectrofotometría Ultravioleta , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinética

RESUMEN

The (+) enantiomer of the very potent and selective dopamine D-2 agonist, 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437), displays partial agonistic activity at dopamine D-2 receptors. In this study (+)N-0437 was investigated for its antagonistic activity at postsynaptic DA receptors in four behavioural tests which are commonly used to evaluate potential neuroleptic activity, i.e. d-amphetamine-induced stereotypy, passive avoidance responding, intracranial self-stimulation behaviour, and catalepsy. (+)N-0437 (25-50 mumol/kg) was active in the first three models, but did not cause catalepsy. Haloperidol, which was used as a reference compound for classical DA antagonists, showed clear activity in all four models at low doses (0.5-1.0 mumol/kg). (-)N-0437, a full D-2 agonist, displayed no activity in these behavioural models. These results suggest that (+)N-0437 could be used to examine the hypothesis that the use of partial agonists could provide a new treatment for schizophrenia.

Asunto(s)

Antipsicóticos , Dopaminérgicos/farmacología , Naftalenos/farmacología , Tetrahidronaftalenos/farmacología , Tiofenos/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/fisiopatología , Dextroanfetamina/farmacología , Haloperidol/farmacología , Masculino , Ratas , Ratas Endogámicas , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/metabolismo , Autoestimulación/efectos de los fármacos , Estereoisomerismo

RESUMEN

1. The disposition and metabolic profiling of 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin(I), a dopamine agonist, were studied in anaesthetized rats after i.v. administration and in non-anaesthetized rats after i.v. and oral dosing. No major differences due to narcosis were observed. 2. Independent of dosing route or anaesthetic, clearance of I was rapid. Bile was the main route of excretion, accounting for 88% dose, compared with 9% in urine. 3. Drug metabolic profiling revealed that I is almost completely metabolized before elimination; less than 0.5% total radioactivity in bile and urine was due to parent compound. 4. The biliary metabolic profiles after i.v. and oral administration were similar. One major metabolite was detected, accounting for 50% (i.v.) or 65% (oral) dose. The major biliary metabolite was identified as the glucuronide of I. 5. Urinary metabolic profiles were quantitatively different from those of bile. After i.v. administration one major metabolite was detected in urine, but this was not the major biliary metabolite. After oral administration, the major urine metabolite was the same as the major biliary metabolite. These differences can be explained by first-pass gastro-intestinal metabolism.

Asunto(s)

Dopaminérgicos/farmacocinética , Naftalenos/farmacocinética , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Administración Oral , Anestesia , Animales , Bilis/metabolismo , Glucuronatos/metabolismo , Infusiones Intravenosas , Masculino , Ratas , Ratas Endogámicas , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/orina , Tiofenos/administración & dosificación , Tiofenos/orina , Distribución Tisular , Tritio

RESUMEN

1. The in vivo metabolic pathways of 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (I) in rats have been established, using in vitro metabolism as a complementary technique. 2. All identified metabolites were conjugates. Glucuronidation at the phenolic group yields the major metabolite, accounting for 50% (i.v.) or 65% (oral) of the dose. The corresponding sulphate conjugate of I is virtually absent (less than 0.2% dose). 3. Hydroxylation of I, at the ortho position to the phenolic hydroxy group, yields 6-hydroxy-I (II), accounting for about 13% (i.v.) or 9% (oral) dose. This catechol is excreted, as a glucuronide, almost exclusively into the bile. Both the 5- and the 6-glucuronide of II were detected in about equal amounts. 4. Metabolism of I in vitro showed that under oxidative conditions, depropylation of I occurred. Conjugation of 3H-I in the presence of UDPGA or PAPS, was successful in yielding the glucuronide and sulphate conjugates.

Asunto(s)

Dopaminérgicos/metabolismo , Naftalenos/metabolismo , Tetrahidronaftalenos/metabolismo , Tiofenos/metabolismo , Administración Oral , Animales , Bilis/metabolismo , Cromatografía Líquida de Alta Presión , Glucuronatos/metabolismo , Hidroxilación , Infusiones Intravenosas , Hígado/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Estructura Molecular , Oxidación-Reducción , Ratas , Ratas Endogámicas , Sulfatos/metabolismo , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/aislamiento & purificación , Tiofenos/administración & dosificación , Tiofenos/aislamiento & purificación

RESUMEN

The potent and selective D2-agonist N-0437 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin undergoes considerable first-pass metabolism due to glucuronidation of the phenolic group after oral administration. In an attempt to improve the bioavailability, eight ester prodrugs of N-0437 were synthesized, i.e. the acetyl, isobutyryl, pivaloyl, benzoyl, 2-methylbenzoyl, 2-methoxybenzoyl, 2,4-dimethylbenzoyl and 2-aminobenzoyl analogues. To examine the hydrolysis rates of these compounds in vitro studies were performed in rat serum. The prodrugs showed a very diverse pattern of hydrolysis rates. The in vivo activities were determined by testing the prodrugs in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used to measure the activity of the compounds. By calculating the area under the curve (AUC), of the time-effect curves of the prodrugs, a significantly improved duration of action was found for those prodrugs which have a slow in vitro hydrolysis rate. However no significant differences in total activity of these slowly hydrolysing prodrugs compared with N-0437 could be demonstrated, although the 2-aminobenzoyl and the 2,4-dimethylbenzoyl derivatives show interesting behavioural profiles. In contrast the isobutyryl ester, a prodrug with a relatively rapid hydrolysis rate, gave an improvement of turning behaviour over the whole time course in comparison with N-0437.

Asunto(s)

Dopaminérgicos/farmacocinética , Naftalenos/farmacocinética , Profármacos , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Animales , Conducta Animal/efectos de los fármacos , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Semivida , Hidrólisis , Hidroxidopaminas/farmacología , Masculino , Oxidopamina , Ratas , Ratas Endogámicas , Técnicas Estereotáxicas , Conducta Estereotipada/efectos de los fármacos