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1.
J Endocrinol Invest ; 39(12): 1419-1424, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27406716

RESUMO

PURPOSE: Poor adherence to recombinant human growth hormone (r-hGH) therapy is associated with reduced growth velocity in children with growth hormone deficiency (GHD). This twelve-month observational study was to assess adherence in r-hGH patients treated with the easypod™, an electronic, fully automated injection device designed to track the time, date and dose administered. METHODS: Ninety-seven prepubertal patients receiving r-hGH therapy were included in the study from ten Italian clinical sites and 88 completed the study. To avoid possible confounding effects, only GHD patients (79/88; 89.7 % of the overall study population) were considered in the final analysis. The primary endpoint-adherence to treatment-was calculated as the proportion of injections correctly administered during the observational period out of the expected total number of injections. The relevant information, tracked by the easypod™, was collected at months 6 (V1) and 12 (V2) after baseline (V0). At study termination, adherence data were partially available from 16 patients and fully available from 53 patients. As secondary endpoints, serum IGF-1 levels, fasting serum glucose and insulin levels and key anthropometric characteristics (height, waist circumference and BMI) were also determined. RESULTS: The easypod™ data showed that 56.7 % of the patients were considered to be fully (≥92 %) adherent to their treatment throughout the period V0-V2. Treatment improved stature, significantly increased IGF-1 and produced a non-significant increase in blood glucose and insulin levels. CONCLUSIONS: The injection-recording system and other characteristics of easypod™ could enhance the ability of physicians to monitor adherence to r-hGH treatment.


Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Nanismo Hipofisário/tratamento farmacológico , Eletrônica/instrumentação , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Adesão à Medicação , Glicemia/análise , Criança , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Estudos Prospectivos
2.
Acta Radiol ; 49(5): 596-601, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18568548

RESUMO

BACKGROUND: Real-time spatial compound imaging (C-US) is an ultrasound (US) method which effectively reduces image artifacts and noise. In contrast to conventional techniques, multiple frames are acquired from different viewing angles and combined to form a single compound image. PURPOSE: To evaluate whether C-US improves ultrasound evaluation of patients with severe Peyronie's disease. MATERIAL AND METHODS: 60 consecutive patients with severe Peyronie's disease underwent conventional US and C-US after intracavernous prostaglandin E1 injection. Corresponding images of the same scan plane were obtained with both methods, and subjective image quality was scored retrospectively using a four-point scale by two blinded readers with different experience in penile imaging. Readers focused on evaluation of the tunica albuginea, plaques, involvement of the penile septum, and overall image quality. Also, presence of large albugineal calcifications or microcalcifications was considered. To assess intrareader agreement, both readers repeated evaluation after a 1-month interval. Statistical analysis was performed using the Wilcoxon signed-rank test and McNemar test. Weighted kappa values were calculated to assess intra- and inter-reader agreement. RESULTS: Average scores were significantly higher for reader 1 (P<0.001). Both readers rated C-US better (P<0.001) than conventional US. Despite higher image quality scores, C-US was as effective as conventional grayscale US in assessing involvement of the penile septum. No differences were found between the two methods for visualization of large calcifications, while microcalcifications were better visible with compound imaging. Intrareader agreement was higher for the more experienced reader 1. CONCLUSION: C-US is subjectively superior to conventional US in evaluating patients with severe Peyronie's disease.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Induração Peniana/diagnóstico , Pênis/diagnóstico por imagem , Humanos , Masculino , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , Processamento de Sinais Assistido por Computador , Ultrassonografia/instrumentação , Ultrassonografia/métodos
3.
J Clin Invest ; 76(4): 1688-91, 1985 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-4056045

RESUMO

It is thought that cysts in polycystic kidneys originate from nephron segments and function in a manner similar to the segment or origin. The indirect evidence for this derives from studies of microanatomy and cyst fluid composition. Cysts with low Na+ have been classified as distal, whereas cysts with high Na+ have been classified as proximal. In order to directly determine the transport characteristics of cyst epithelium, cysts from a human polycystic kidney were studied in vitro using Ussing chamber techniques. Composition of cyst fluid was determined in parallel with these studies. Cysts with low Na+ (gradient cysts) demonstrate characteristics consistent with distal nephron origin including elevated potential difference (PD), short-circuit current (Isc), and low conductance. PD and Isc of gradient cysts were amiloride sensitive. Nongradient cysts, however, require additional characterization. At least two types of nongradient cysts were identified, one with characteristics consistent with proximal nephron origin and another apparently without function. These studies are the first direct evidence for active transport of cysts from human polycystic kidney and provide strong evidence to support the concept that cysts function in the same manner as the nephron segment of origin.


Assuntos
Doenças Renais Policísticas/patologia , Amilorida/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/ultraestrutura , Humanos , Túbulos Renais Distais , Túbulos Renais Proximais , Masculino , Pessoa de Meia-Idade , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/fisiopatologia , Sódio/metabolismo
4.
Chem Commun (Camb) ; 53(14): 2268-2271, 2017 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-28149992

RESUMO

Aggregation, red-NIR emission and light-up upon nucleic acid G-quadruplex binding have been investigated for a prototype core-extended naphthalene diimide, which is capable of fast cellular entry and nucleolar localization. Both high-level colocalization with an anti-G-quadruplex antibody and nucleolin displacement reveal that the compound targets and thus makes visible nuclear DNA G-quadruplexes.


Assuntos
Corantes Fluorescentes/química , Quadruplex G , Anticorpos/química , Anticorpos/imunologia , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proteínas Cromossômicas não Histona/imunologia , Corantes Fluorescentes/metabolismo , Células HEK293 , Humanos , Imidas/química , Imidas/metabolismo , Microscopia Confocal , Naftalenos/química , Naftalenos/metabolismo , Espectrometria de Fluorescência
5.
Plant Biol (Stuttg) ; 17(2): 505-11, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25262834

RESUMO

Posidonia oceanica is the most common, widespread and important monocotyledon seagrass in the Mediterranean Basin, and hosts a large biodiversity of species, including microorganisms with key roles in the marine environment. In this study, we ascertain the presence of a fungal endophyte in the roots of P. oceanica growing on different substrata (rock, sand and matte) in two Sicilian marine meadows. Staining techniques on root fragments and sections, in combination with microscope observations, were used to visualise the fungal presence and determine the percentage of fungal colonisation (FC) in this tissue. In root fragments, statistical analysis of the FC showed a higher mean in roots anchored on rock than on matte and sand. In root sections, an inter- and intracellular septate mycelium, producing intracellular microsclerotia, was detected from the rhizodermis to the vascular cylinder. Using isolation techniques, we obtained, from both sampling sites, sterile, slow-growing fungal colonies, dark in colour, with septate mycelium, belonging to the dark septate endophytes (DSEs). DNA sequencing of the internal transcribed spacer (ITS) region identified these colonies as Lulwoana sp. To our knowledge, this is the first report of Lulwoana sp. as DSE in roots of P. oceanica. Moreover, the highest fungal colonisation, detected in P. oceanica roots growing on rock, suggests that the presence of the DSE may help the host in several ways, particularly in capturing mineral nutrients through lytic activity.


Assuntos
Alismatales/microbiologia , Ascomicetos/fisiologia , Endófitos , Raízes de Plantas/microbiologia , Ascomicetos/genética , Ascomicetos/isolamento & purificação , Itália , Mar Mediterrâneo , Dados de Sequência Molecular
6.
Cell Calcium ; 17(5): 375-83, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-7553790

RESUMO

The mechanisms that regulate ion and fluid transport by the human intrahepatic bile duct have not been well defined. Human intrahepatic biliary cell lines that we have developed were used to identify and characterize purinoceptors based on increases in intracellular calcium in response to ATP and other nucleotides. Intracellular free calcium was measured in cell suspensions using the fluorescent probe Fura-2 and a fluorescence spectrophotometer. Halide efflux was measured in single cells using fluorescence microscopy and the fluorescent probe SPQ. Intracellular calcium increases equivalently in response to ATP and UTP, peaking, then diminishing to a new, elevated baseline. The peak elevation of calcium is the result of both the release of intracellular stores of calcium and the influx of extracellular calcium. The purinoceptor P2U-subtype was identified based on the potency rank order of ATP-analogues. Halide efflux increases with P2U-purinoceptor stimulation which is consistent with the opening of a Ca(2+)-sensitive Cl- channel. The physiological significance of P2U-purinoceptor activation and its effect on the ionic content and flow rate of bile remains to be determined.


Assuntos
Ductos Biliares Intra-Hepáticos/metabolismo , Cálcio/metabolismo , Canais de Cloreto/metabolismo , Receptores Purinérgicos P2/fisiologia , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Ductos Biliares Intra-Hepáticos/citologia , Transporte Biológico , Cálcio/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Células Epiteliais , Fura-2 , Humanos , Ionomicina/farmacologia , Organelas/metabolismo , Receptores Purinérgicos P2/biossíntese , Espectrometria de Fluorescência , Uridina Trifosfato/metabolismo , Uridina Trifosfato/farmacologia
7.
Endocrinology ; 121(2): 645-9, 1987 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-3496214

RESUMO

After adrenal enucleation (AE) rats avidly retain sodium (early phase), but after 7-10 days they lose this sodium avidity (late phase). Although increased production of a mineralocorticoid, 19-nor-deoxycorticosterone (19-Nor-DOC), has been implicated, 19-Nor-DOC levels during the early and late phases of AE have not been systematically measured. Furthermore it is not known why 19-Nor-DOC production should increase during a time when production of 11 beta- and 18-hydroxylated corticosteroids are decreased in AE. The purpose of this study was to examine the 11 beta, 18-, and 19-hydroxylase pathways in the early and late phases of AE. The results demonstrate increased urinary 19-Nor-DOC and decreased 18-OH-DOC and corticosterone excretion in the early phase of AE at a time when adrenal mitochondrial 11 beta- and 18-hydroxylase activities were decreased but 19-hydroxylase activity was unchanged. During the late phase of AE, urinary 19-Nor-DOC had decreased and 18-OH-DOC and corticosterone had increased to levels indistinguishable from those in sham controls. This reduction in 19-Nor-DOC was associated with a decrease in 19-hydroxylase activity in AE. Since the 11 beta, 18-, and 19-hydroxylases have a common substrate (DOC), it is possible that differential flux of DOC through these pathways could account for the changes in steroid production in AE. These data suggest that the increased 19-Nor-DOC excretion in AE may be due to alterations in enzyme activity leading to a shunting of DOC into the 19-Nor-DOC pathway. In addition, the synchronicity of 19-Nor-DOC with sodium excretion suggests that it has an important role in the pathogenesis of the sodium retention in AE.


Assuntos
Glândulas Suprarrenais/enzimologia , Adrenalectomia , Sistema Enzimático do Citocromo P-450/metabolismo , Desoxicorticosterona/análogos & derivados , Esteroide Hidroxilases/metabolismo , Animais , Corticosterona/urina , Citocromo P-450 CYP11B2 , Desoxicorticosterona/urina , Masculino , Mitocôndrias/enzimologia , Ratos , Esteroide 11-beta-Hidroxilase/metabolismo
8.
J Med Chem ; 43(2): 270-7, 2000 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-10649982

RESUMO

N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (1), a high-affinity and selective dopamine D(4) receptor ligand, was chosen as a lead, and structural modifications were done on its amide bond and on its alkyl chain linking the benzamide moiety to the piperazine ring and by preparing some semirigid analogues. The binding profile at dopamine D(4) and dopamine D(2), serotonin 5-HT(1A), and adrenergic alpha(1) receptors of 16 new compounds was determined. From the results emerged that the modification of the amide bond and the elongation of the intermediate alkyl chain caused a decrease in dopamine D(4) receptor affinity. All prepared semirigid analogues displayed D(4) receptor affinity values in the same range of the opened counterparts.


Assuntos
Benzamidas/química , Dopaminérgicos/química , Piperazinas/química , Receptores de Dopamina D2/metabolismo , Animais , Benzamidas/metabolismo , Benzamidas/farmacologia , Dopaminérgicos/metabolismo , Dopaminérgicos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Piperazinas/metabolismo , Piperazinas/farmacologia , Ratos , Receptores de Dopamina D4 , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
9.
J Med Chem ; 41(24): 4903-9, 1998 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-9822559

RESUMO

A series of new 1-aryl-4-alkylpiperazines containing a terminal benzamide fragment or a tetralin-1-yl nucleus on the alkyl chain were synthesized and tested for binding at cloned human dopamine D4 and D2 receptor subtypes. A SAFIR (structure-affinity relationship) study on this series is herein discussed. The most relevant D4 receptor affinities were displayed by N-[omega-[4-arylpiperazin-1-yl]alkyl]-methoxybenzamides (compounds 5, 16-20), their IC50 values ranging between 0.057 and 7.8 nM. Among these, N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (17) emerged since it exhibited very high affinity for dopamine D4 receptor (IC50 = 0.057 nM) with selectivity of >10 000 for the D4 versus the D2 receptor; compound 17 was also selective versus serotonin 5-HT1A and adrenergic alpha1 receptors.


Assuntos
Benzamidas/síntese química , Piperazinas/síntese química , Receptores de Dopamina D2/metabolismo , Animais , Benzamidas/química , Benzamidas/metabolismo , Linhagem Celular , Córtex Cerebral/metabolismo , Humanos , Insetos , Ligantes , Piperazinas/química , Piperazinas/metabolismo , Ensaio Radioligante , Ratos , Receptores de Dopamina D2/biossíntese , Receptores de Dopamina D4 , Relação Estrutura-Atividade
10.
J Med Chem ; 42(3): 490-6, 1999 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-9986719

RESUMO

Some 1-aryl-4-[(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-propyl]piperazines and their alkylamino and alkylamido analogues, previously studied as 5-HT1A ligands, were prepared in enantiomerically pure form, and their absolute configuration was determined by chemical correlation or by chiroptical properties. They were evaluated for in vitro 5-HT1A, D2, and alpha1 receptor affinity by radioligand binding assays, to study the influence of the chiral carbon atom of the tetrahydronaphthalene nucleus on the 5-HT1A affinity and selectivity. Results indicated that, as regarding the 5-HT1A receptor affinity, there was no difference in affinity between (-)- and (+)-enantiomers as well as the racemate of each compound. The stereochemistry, instead, influenced the selectivity: all (-)-enantiomers displayed affinity values higher than those of (+)-isomers at D2 receptors, and conversely, all (+)-enantiomers displayed affinity values higher than those of (-)-isomers at alpha1 receptors. As a result of this trend, it is not possible to predict the isomer with a better selectivity profile. However, compounds (S)-(+)-2, (S)-(+)-4, and (R)-(+)-6 displayed high affinity for the 5-HT1A receptor (IC50 values ranging between 7.0 and 2.3 nM) and good selectivity (>/=250-fold) versus both D2 and alpha1 receptors. Furthermore, compounds (S)-(+)-4 and (R)-(-)-4 were submitted to the [35S]GTPgammaS binding assay for a preliminary evaluation of their intrinsic activity on the 5-HT1A receptor.


Assuntos
Piperazinas/química , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Tetra-Hidronaftalenos/química , Animais , Células CHO , Cricetinae , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Espectroscopia de Ressonância Magnética , Piperazinas/metabolismo , Ensaio Radioligante , Receptores 5-HT1 de Serotonina , Estereoisomerismo , Relação Estrutura-Atividade
11.
J Med Chem ; 39(1): 176-82, 1996 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-8568804

RESUMO

Two series of compounds that are structurally related to benzomorphans, derived by structural modification of arylpiperazines with high 5-HT1A affinity and moderate sigma affinity, were prepared in order to increase sigma affinity and selectivity. All new compounds are N-substituted-omega-(1,2,3,4-tetrahydronaphthalen-1-yl)- or -omega-(1,2-dihydronaphthalen-4-yl)-n-alkylamines with, in some cases, a methoxy group on the tetralin moiety. They were tested in radioligand binding assays on sigma ([3H]DTG and [3H]-(+)-pentazocine), D-2 dopaminergic, 5-HT1A and 5-HT2 serotonergic, and PCP (phencyclidine) receptors. A first set of compounds bearing a 4-(1-substituted)piperazine moiety as terminal fragment on the alkyl chain showed moderate to high sigma affinity (Ki = 5.3-139 nM), the most active and selective being 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl ]piperazine (14), with probable pronounced sigma 2 affinity (Ki = 5.3 nM on [3H]DTG and Ki = 71 nM on [3H]-(+)-pentazocine). Moreover, compound 13, a 1-benzylpiperazine analogue of 14, preserved a dual high 5-HT1A and sigma affinity (Ki = 3.6 nM on [3H]-5-HT and Ki = 7.0 nM on [3H]DTG). The second set of compounds includes some N-phenylalkyl derivatives of 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)- n-propylamine that can be considered to be open-chain derivatives of 4-substituted-1-arylpiperazines. Among these compounds that had a lower activity toward sigma binding sites, a high 5-HT1A affinity was found for the N-(3-phenylpropyl) derivative 21 (Ki = 4.4 nM) which demonstrated very good selectivity.


Assuntos
Piperazinas/metabolismo , Propilaminas/metabolismo , Receptores de Serotonina/metabolismo , Receptores sigma/metabolismo , Agonistas do Receptor de Serotonina/metabolismo , Tetra-Hidronaftalenos/metabolismo , Analgésicos Opioides/síntese química , Analgésicos Opioides/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cobaias , Espectroscopia de Ressonância Magnética , Masculino , Pentazocina/farmacologia , Fenciclidina/metabolismo , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Propilaminas/síntese química , Propilaminas/química , Propilaminas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores da Fenciclidina/metabolismo , Receptores 5-HT1 de Serotonina , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia
12.
J Med Chem ; 35(16): 3045-9, 1992 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-1354263

RESUMO

Some substituted 3-phenylmorpholines (10a-e,j,k) and 3-thienylmorpholines (10f,g), isosteres of 3-(3-hydroxy-phenyl)-N-n-propylpiperidine (3-PPP), were prepared and submitted to binding assays on D-2 dopaminergic and 5-HT1 and 5-HT2 serotonergic receptors, in comparison with 3-PPP and its analogue 3a,b. The results show the loss of D-2 affinity for all morpholines, while a certain activity was still observable for piperidine derivatives. Regarding the serotonergic affinity, only chloro and methoxy derivatives (10a-d) were moderately active on the 5-HT1A receptor, either when the substituent was in the C-2 or C-3 position, whereas no tested compounds showed affinity toward the 5-HT2 receptor.


Assuntos
Dopaminérgicos/química , Oxigênio/química , Piperidinas/química , Animais , Encéfalo/metabolismo , Dopaminérgicos/metabolismo , Técnicas In Vitro , Ketanserina/metabolismo , Camundongos , Piperidinas/metabolismo , Ensaio Radioligante , Ratos , Ratos Endogâmicos , Receptores de Serotonina/metabolismo , Espiperona/metabolismo
13.
J Med Chem ; 39(21): 4255-60, 1996 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-8863803

RESUMO

A series of substituted N-[(tetralin-1-yl)alkyl]piperidines and a number of related N-di-n-propyl-[(tetralin-1-yl)alkyl]amines were prepared. Structural modifications such as piperidine substitutions, intermediate chain lengthening, and the nature of the aromatic ring were explored in order to identify structural requirements for selective sigma 1 affinity. They were tested in radioligand binding assays on sigma 1, 5-HT1A and 5-HT2 serotonergic, PCP (phencyclidine), and D-2 dopaminergic receptors. Almost all the compounds reported here showed a high to superpotent sigma 1 affinity, and some compounds also demonstrated a widespread selectivity over the other receptors. In [3H]-(+)-pentazocine binding, 3,3-dimethyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl] piperidine (24) and 3,3-dimethyl-1-[4-(1,2,3,4-tetrahydronaphthalen-1-yl)-n- butyl]piperidine (26) reached the lowest Ki values (0.4 and 0.8 nM, respectively); compound 24 also demonstrated a considerable PCP affinity (Ki = 34.2 nM), whereas compound 26 was suitably selective. Furthermore the presence of a 4-benzyl substituent on the piperidine ring (compound 16, Ki = 3.9 nM on sigma 1 sites) caused an increase in 5-HT1A affinity (Ki < 0.14 nM).


Assuntos
Piperidinas/química , Receptores sigma/metabolismo , Tetra-Hidronaftalenos/química , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ketanserina/metabolismo , Fenciclidina/metabolismo , Piperidinas/farmacologia , Ratos , Receptores da Fenciclidina/metabolismo , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina , Espiperona/metabolismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacologia
14.
J Med Chem ; 39(16): 3195-202, 1996 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-8759642

RESUMO

The synthesis and binding profile on 5-HT1A, 5-HT2, D-1, D-2, alpha 1, and alpha 2 receptors of the N-4 long-chain arylpiperazines 22-40 are reported, where an amino or amido function is inserted into the intermediate chain linked to the alpha position of the tetralin nucleus. Unlike the buspirone analogues, for the amido derivatives studied in this paper, the terminal amide function of long-chain piperazines is not important for 5-HT1A receptor affinity binding, and its removal yields high-affinity 5-HT1A receptor agents.


Assuntos
Piperazinas/síntese química , Piperazinas/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/metabolismo , Animais , Buspirona/análogos & derivados , Buspirona/farmacologia , Espectrometria de Massas , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica , Ratos , Receptores Adrenérgicos/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores 5-HT1 de Serotonina , Serotonina/farmacologia , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia
15.
J Med Chem ; 41(21): 3940-7, 1998 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-9767631

RESUMO

Several 3, 3-dimethyl-N-[omega-(tetrahydronaphthalen-1-yl)alkyl]piperidine derivatives and some related compounds were prepared. Their affinities and sigma-subtype selectivities were investigated by radioligand binding assays, labeling sigma1 receptors with [3H]-SKF 10047 and sigma2 receptors with [3H]-DTG. Many tested compounds bound sigma1 and/or sigma2 receptors with nanomolar or subnanomolar IC50 values. Compound (+)-22, (+)-3,3-dimethyl-1-[3-(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-propyl]piperidine, was the most potent (IC50 = 0.089 nM) and selective sigma1 ligand (1340-fold), showing a 10-fold enantioselectivity. Compounds 29 (3, 3-dimethyl-1-[4-(6-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-butyl]piperidine) and 31 (3, 3-dimethyl-1-[5-(1,2,3, 4-tetrahydronaphthalen-1-yl)-n-pentyl]piperidine) were highly potent (IC50 = 0.016 nM and IC50 = 0.008 nM, respectively) and highly selective sigma2 ligands (more than 100000-fold).


Assuntos
Piperidinas/química , Piperidinas/síntese química , Receptores sigma/metabolismo , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/síntese química , Animais , Encéfalo/metabolismo , Masculino , Piperidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/metabolismo , Receptor Sigma-1
16.
J Med Chem ; 38(6): 942-9, 1995 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-7699710

RESUMO

Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines). Several synthetic procedures were followed to obtain the final products, depending on the presence or absence of a double bond, as well as of a heteroatom on the side chain. In the first case versatile use of Grignard reaction was made, whereas in the second one usual synthetic ways were applied. Final compounds were evaluated for in vitro activity on dopamine D-1 and D-2, serotonin 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2, alpha 1 adrenergic, and sigma receptors by radioreceptor binding assay. For the 2-MeO-Ph, 2-pyridyl, and unsubstituted phenyl N-piperazine derivatives, low IC50 values (0.3 nM) on 5-HT1A receptors and high selectivity values were observed.


Assuntos
Piperazinas/síntese química , Piperazinas/metabolismo , Receptores de Serotonina/metabolismo , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/metabolismo , Animais , Fenômenos Químicos , Físico-Química , Cobaias , Isomerismo , Cinética , Masculino , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/efeitos dos fármacos , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacologia
17.
J Med Chem ; 39(25): 4928-34, 1996 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-8960552

RESUMO

The synthesis of 1-phenylpiperazines, linked in the alpha or beta position of the tetralin moiety on the terminal part of the N-4 alkyl chain, and their radioligand binding affinities for 5-HT(1A), 5-HT(2A), D-1, D-2, alpha1, and alpha2 receptors along with SAR studies on the 5-HT(1A) receptor are reported. Several changes have been carried out on previous structures of type 2, by inserting the alkyl chain with variable length in the alpha or beta position of the tetralin moiety and by changing the position of the methoxy group on the aromatic ring of the tetralin nucleus. The highest affinity (IC50 = 0.50 nM) and selectivity for the 5-HT(1A) receptor were showed by 1-phenylpiperazine 2a with a three-membered alkyl chain bearing a 5-methoxytetralin-1-yl ring in the omega position.


Assuntos
Piperazinas/metabolismo , Receptores de Serotonina/metabolismo , Espectroscopia de Ressonância Magnética , Piperazinas/química , Ensaio Radioligante , Relação Estrutura-Atividade
18.
J Med Chem ; 37(1): 99-104, 1994 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-8289207

RESUMO

A new model of 4-alkyl-1-arylpiperazines containing a terminal dihydronaphthalene fragment on the alkyl chain was synthesized in order to have mixed serotonergic and dopaminergic activity and to pursue the recent alternative approaches to the discovery of novel antipsychotic and anxiolytic agents. Title compounds were evaluated for in vitro activity on dopamine D-2 and serotonin 5-HT1A and 5-HT2 receptors by radioreceptor binding assays. They show high nanomolar affinity for 5-HT1A, moderate affinity for D-2, and low affinity for 5-HT2 receptors, and in particular, two compounds, 4-[3-(1,2-dihydro-6-methoxynaphthalen-4-yl)-n-propyl]-1-(2- methoxyphenyl)piperazine (8) and 4-[3-(1,2-dihydro-8-methoxynaphthalen-4-yl)-n-propyl]-1-(2- pyridyl)piperazine (15), show values (nM) of IC50 = 2.0 and 1.4 for 5-HT1A and IC50 = 90.6 and 119.3 for D-2, respectively. Some in vivo behavioral studies show compound 8 to be an antagonist on 5-HT1A receptors. These first findings place the new arylpiperazines on the same level as that of the azaspirone class, e.g., 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)-n-butyl]piperazine (NAN-190) and buspirone.


Assuntos
Naftalenos/síntese química , Piperazinas/síntese química , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo , Animais , Membrana Celular/metabolismo , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Ketanserina/metabolismo , Masculino , Estrutura Molecular , Naftalenos/farmacologia , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/fisiologia , Receptores de Serotonina/fisiologia , Espiperona/metabolismo , Relação Estrutura-Atividade , Trítio
19.
J Med Chem ; 44(25): 4431-42, 2001 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-11728188

RESUMO

The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D2, and alpha1 receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K(i), nM: 5-HT1A = 0.028, D2 = 2194, alpha1 = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D2, and alpha1 receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D2 and alpha1 receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha1a, alpha1b, alpha1d receptor subtypes. They were also submitted to the [35S]GTPgammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K(i)) and in vitro activity (pD'2) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.


Assuntos
Etilaminas/síntese química , Piperazinas/síntese química , Piridinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/síntese química , Animais , Encéfalo/metabolismo , Etilaminas/química , Etilaminas/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Células HeLa , Humanos , Técnicas In Vitro , Ligantes , Conformação Molecular , Piperazinas/química , Piperazinas/metabolismo , Piridinas/química , Piridinas/metabolismo , Ensaio Radioligante , Ratos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Transfecção
20.
J Nucl Med ; 39(12): 2158-61, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9867161

RESUMO

Sensitive and specific, whole-body 131I scintigraphy remains an important technique for diagnosing metastases from differentiated papillary or follicular thyroid carcinoma. False-positive 131I localization is well recognized and can occur in a variety of conditions. We present a case of intense 131I localization in a previously unsuspected large renal cyst; the lesion was not visualized on routine preablation diagnostic 131I scintigraphy but was obvious on post-therapeutic whole-body imaging, underscoring the value of post-therapy imaging in detecting abnormalities not apparent on diagnostic studies. Radioiodine within the urinary bladder or, at times, the renal collecting system is expected, because 131I excretion is primarily by glomerular filtration. In the case presented here, 131I activity within the renal cyst supports the concept that iodide is subject to an active secretory process by the renal tubule.


Assuntos
Radioisótopos do Iodo , Doenças Renais Císticas/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Carcinoma Papilar/diagnóstico por imagem , Carcinoma Papilar/cirurgia , Reações Falso-Positivas , Taxa de Filtração Glomerular , Humanos , Radioisótopos do Iodo/farmacocinética , Doenças Renais Císticas/complicações , Masculino , Pessoa de Meia-Idade , Radiografia , Compostos Radiofarmacêuticos/farmacocinética , Pentetato de Tecnécio Tc 99m/farmacocinética , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Tomografia Computadorizada de Emissão de Fóton Único , Ultrassonografia
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