RESUMEN
Abstract: The first act of assisted suicide in Italy was recently carried out. This event is an absolute novelty for the country, affected by recent legislative changes aimed only at introducing the right to interrupt health treatments and, therefore, carry out exclusively omissive end-of-life acts. These normative provisions lay their foundations in a cultural context centered on the protection of the right to life and health; however, the cases that have occurred over time, including the famous story of DJ Fabo, have led the Constitutional Court to re-evaluate these dictates, introducing in 2019 the right to resort to assisted suicide procedures within well-defined areas, including incurability of the condition, the serious suffering of the individual and the retained ability to stand trial. The case addressed concerns a quadriplegic subject who was the victim of a road accident. Following consultation with a specialized institution, the subject made the decision to undergo an assisted sui-cide procedure in Italy. Having obtained the authorization from the competent authorities, he started a fundraiser to finance the devices and drugs required and, finally, he died. The opening by Italy towards the assisted suicide procedure represents a great step towards a broad context, as well as a decisive act for the purpose of protecting the right to self-determination of the individual. However, the current legislative framework presents significant criticalities and shortcomings. In first place, the dissonance between the laws in force and the judicial sentences is likely to generate problems of uneven application of the rules in a country dominated by the principle of Civil Law. Furthermore, the need for the applicant to fully self-finance the procedure clearly clashes with the constitutional principle of free access to care. Then emerges the need for a guideline document regarding the completion of the procedure itself, the times, methods and drugs implied, in order to significantly reduce the decision-making process by the ethics committees that still weighs on each individual case. Finally, conside-ring what has been observed on the subject of voluntary termination of pregnancy, it is necessary to ask what will be the general orientation of the doctors called to perform the act and whether they will be given the opportunity to express their refusal. The case analyzed could represent the beginning of a new era for Italian culture, but the large-scale application of assisted suicide procedures requires the introduction of legislative provisions that definitively eliminate the critical issues that have emerged so far.
Asunto(s)
Suicidio Asistido , Humanos , Masculino , Muerte , Pueblo Europeo , Italia , Autonomía Personal , Suicidio Asistido/legislación & jurisprudenciaRESUMEN
Background: Nowadays it is estimated that worldwide more than 700 000 people die by suicide every year and a greater amount attempt this practice. Suicide is the fourth cause of death among 15-29 years old people. Sodium Hypochlorite (NaOCl) is used in household and com-mercial bleaches and due to its easy availability, accidental exposure to or intentional ingestion of NaOCl occurs frequently. In most cases health effects are only transient but if the subject ingests a large amount of this substance, this can generate severe consequences as oesophageal or stomach lesions and electrolytic imbalance. In the present study we analyse a rare case of suicide by fatal ingestion of bleach. Case Report: Case of a caucasic 47 years old woman with a background of several suicide attempts by exogenous substance ingestion that was found death alone in her apartment. The purpose of our investigation was identifying the cause of death. A rigorous and multidisciplinary methodological approach was adopted, including an accurate judicial inspection of the environment, an anamnestic collection, an autoptic procedure completed by macro and microscopic examinations of internal organs and a toxicological examination of biological fluids. Furthermore, a literature overview of similar cases was carried out. The resulting evidence demonstrates that woman's death occurred after a massive bleach ingestion. Conclusions: This case report highlights the importance of forensic methodology in investigating the ingestion of exogenous substances. Crime scene investigation, a detailed post-mortem examination, toxicology and a complete histopathological study are mandatory to solve the enigma.
Asunto(s)
Hipoclorito de Sodio , Suicidio Completo , Humanos , Femenino , Persona de Mediana Edad , Hipoclorito de Sodio/envenenamiento , Resultado Fatal , Blanqueadores/envenenamientoRESUMEN
Background: In the healthcare system, in the last 30 years, the prognostically negative value of the so-called Weekend Effect (WE) has been internationally recognized. The WE is regarded as the increased risk a patient might incur when hospitalized during non-working days, of enduring severe complications in comparison to the same hospitalization that occur on working days. The aim of this study was to retrospectively verify whether, once a mistake was made during weekends or on holidays, in comparison to a mistake occurred on workdays, it subsequently implied a higher risk of complications, death included, in a statistical and medico-legal way. Methods: Three different evaluators independently examined a total of 378 medico-legal cases over a more than 20-year period. Eventual medical actions and omissions were labelled as 'mistake' when the AJ claimed that at least one occurred; 'alleged mistake' included the cases where the EW's report disagreed with the AJ's one; finally, 'no mistake' when both the AJ and the EW agreed in their evaluations. During weekends there is a higher risk that a mistake occurs (OR=3.3, 95% CI=1.6;7.4; p-value<0.001) compared to weekdays. When death occurs, delayed diagnosis is the main cause (p=0.02), whereas a damaging action is more frequently claimed in general. Conclusions: We verified as actual the impact of the WE on patients' outcome from a medico-legal point of view. The implications for an improvement of the several settings of the Italian NHS are various, and many are the consequences in the healthcare management.
Asunto(s)
Errores Médicos , Calidad de la Atención de Salud , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atención Posterior/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Italia , Mala Praxis/estadística & datos numéricos , Mala Praxis/legislación & jurisprudencia , Errores Médicos/estadística & datos numéricos , Errores Médicos/legislación & jurisprudencia , Estudios Retrospectivos , Factores de TiempoRESUMEN
Background: The voluntary interruption of pregnancy (VIP) remains one of the most contentious issues worldwide, subject to different legal frameworks and cultural interpretations. Access to VIP is considered a fundamental right for women, recognized by international organizations such as the World Health Organization (WHO) and supported by the United Nations. It is estimated that 40-50 million abortions are performed each year, of which about 75% are in developing countries. IVG is legal in only 25 countries, while in the others, it is severely restricted or illegal, leading to an increase in risky and illegal practices. Methods: We consulted government and ministerial websites in European countries to gather data on current abortion laws. In addition, scientific articles and legislative documents compare regulations across some countries, especially from 2020 to today, analyzing differences, similarities and implications. Percentage data on the number of abortions in several European countries, including Italy, were analyzed. Conclusion: Our analysis revealed significant differences in abortion laws between European countries. In many countries, abortion is allowed at the request of the woman within a certain gestational age limit, which typically ranges between 10 and 24 weeks. However, in some countries, the restrictions are much stricter, with limitations making access to legal abortion very difficult or impossible. In conclu-sion, the Italian experience highlights the importance of considering local sociocultural dynamics in shaping IVG policies and highlights the need for an evidence-based approach to guarantee women right to reproductive health internationally, surrounding reproductive rights, gender equality, and public health policy.
Asunto(s)
Aborto Legal , Humanos , Femenino , Embarazo , Italia , Europa (Continente) , Aborto Legal/legislación & jurisprudencia , Aborto Legal/estadística & datos numéricos , Aborto Inducido/legislación & jurisprudencia , Aborto Inducido/estadística & datos numéricosRESUMEN
BACKGROUND/AIMS: The role of resistin, an adipocyte-secreted hormone, in insulin resistance and in inflammation is controversial. In chronic hepatitis C, insulin resistance, type 2 diabetes and liver steatosis are frequent and inconsistently correlated to circulating resistin levels. In this study we assessed if viral aetiology and host metabolic parameters influence serum resistin in patients with HCV- and HBV- related chronic hepatitis. METHODOLOGY: Serum resistin was measured by ELISA and correlated to viral aetiology, age, gender, BMI, HOMA-IR, liver steatosis, hepatitis staging and grading, blood glucose, triglycerides and cholesterol in 43 patients with chronic hepatitis C, in 16 with chronic hepatitis B and in 29 healthy controls. RESULTS: In both groups of patients resistin was significantly higher than in controls, with higher values in HBV- than in HCV-patients (p = 0.0007). Resistin levels were correlated to aetiology and, inversely, to age (p = 0.026), diabetes (p = 0.036) and steatosis (p = 0.029). Multiple regression analysis showed that resistin concentration was dependent only on the aetiology of liver disease (p = 0.001). CONCLUSIONS: In chronic viral hepatitis serum resistin levels are high and not associated with altered metabolic parameters or with the histological activity of the disease. The meaning of higher resistin in HBV- than in HCV- chronic hepatitis is unclear.
Asunto(s)
Hepatitis B Crónica/sangre , Hepatitis C Crónica/sangre , Enfermedades Metabólicas/diagnóstico , Resistina/sangre , Adulto , Anciano , Biomarcadores , Índice de Masa Corporal , Femenino , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana EdadRESUMEN
AIM: In several studies, attention is needed to one specific complication, in particularly to hepatocellular carcinoma, which modifies the natural history of liver cirrhosis. Thus, we performed a retrospective cohort analysis to clarify which complications, alone or in combination, are predictive factors of mortality in patients with viral or alcoholic cirrhosis without hepatocellular carcinoma. METHODS: Case records of 255 patients with decompensated viral or alcoholic cirrhosis between January 1990 and December 2000 were retrospectively analyzed. Relevant clinical and laboratory parameters, and their relationship to mortality, were studied. RESULTS: The mean duration of follow-up period was 29 months in which 178 patients (69.8%) died and 77 (31.8%) survived. None of the patients underwent liver transplantation. The cumulative mortality rate of patients with complicated cirrhosis was 38.8% after 1 year, 51.7% after 2 years, 61.1% after 3 years and 65.1% after 8 years. A multivariate Cox's model identified the following variables as significant: age (P=0.001), gastrointestinal bleeding (GB)-ascites combination (P=0.000), encephalopathy-GB-ascites (P=0.028), hepatorenal syndrome (HRS) (P=0.000), GB-spontaneous bacterial peritonitis (SBP) (P=0.001), alkaline phosphatase (ALP) (P=0.004) and the Child-Pugh score (P=0.000). CONCLUSION: The mortality in a group of patients with alcoholic cirrhosis is longer than in those with viral cirrhosis . Moreover, ascites in combination with other complications, HRS and hemorrage-SBP association are independent predictors of mortality in patients with complicated liver cirrhosis.
Asunto(s)
Cirrosis Hepática Alcohólica/mortalidad , Cirrosis Hepática/mortalidad , Cirrosis Hepática/virología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Estudios de Seguimiento , Hepatitis B/complicaciones , Hepatitis B/diagnóstico , Hepatitis C/complicaciones , Hepatitis C/diagnóstico , Humanos , Estimación de Kaplan-Meier , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Cirrosis Hepática Alcohólica/complicaciones , Cirrosis Hepática Alcohólica/diagnóstico , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND AND PURPOSE: The 2-propyl-1,4 benzoxazine (AM10) shows a peculiar behaviour in skeletal muscle, inhibiting or opening the ATP-sensitive K(+) (KATP) channel in the absence and presence of ATP, respectively. We focused on tissue selectivity and mechanism of action of AM10 by testing its effects on pancreatic KATP channels by means of both in vitro and in vivo investigations. EXPERIMENTAL APPROACH: In vitro, patch-clamp recordings were performed in native pancreatic beta cells and in tsA201 cells expressing the Kir6.2 Delta C36 channel. In vivo, an intraperitoneal glucose tolerance test was performed in normal mice. KEY RESULTS: In contrast with what observed in the skeletal muscle, AM10, in whole cell perforated mode, did not augment KATP current (I(KATP)) of native beta cells but it inhibited it in a concentration-dependent manner (IC(50): 11.5 nM; maximal block: 60%). Accordingly, in current clamp recordings, a concentration-dependent membrane depolarization was observed. On excised patches, AM10 reduced the open-time probability of KATP channels without altering their single channel conductance; the same effect was observed in the presence of trypsin in the bath solution. Moreover, AM10 inhibited, in an ATP-independent manner, the K(+) current resulting from expressed Kir6.2 Delta C36 (maximal block: 60% at 100 microM; IC(50): 12.7 nM) corroborating an interaction with Kir. In vivo, AM10 attenuated the glycemia increase following a glucose bolus in a dose-dependent manner, without, at the dose tested, inducing fasting hypoglycaemia. CONCLUSION AND IMPLICATIONS: Altogether, these results help to gain insight into a new class of tissue specific KATP channel modulators.
Asunto(s)
Adenosina Trifosfato/farmacología , Aminopiridinas/farmacología , Benzoxazinas/farmacología , Glucemia/efectos de los fármacos , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna/efectos de los fármacos , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Humanos , Técnicas In Vitro , Células Secretoras de Insulina/metabolismo , Activación del Canal Iónico/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Ratones , Mutación , Técnicas de Placa-Clamp , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio de Rectificación Interna/metabolismo , Valores de Referencia , Factores de Tiempo , TransfecciónRESUMEN
BACKGROUND AND PURPOSE: Mexiletine (Mex), an orally effective antiarrhythmic agent used to treat ventricular arrhythmias, has also been found to be effective for myotonia and neuropathic pain. It is extensively metabolized in humans but little information exists about the pharmacodynamic properties of its metabolites. EXPERIMENTAL APPROACH: To determine their contribution to the clinical activity of Mex, p-hydroxy-mexiletine (PHM), hydroxy-methyl-mexiletine (HMM), N-hydroxy-mexiletine (NHM) (phase I reaction products) and N-carbonyloxy beta-D-glucuronide (NMG) (phase II reaction product) were tested on sodium currents (I(Na)) of frog skeletal muscle fibres. Sodium currents were elicited with depolarizing pulses from different holding potentials (HP=-140, -100, -70 mV) and stimulation frequencies (0.25, 0.5, 1, 2, 5, 10 Hz) using the vaseline-gap voltage-clamp method. KEY RESULTS: All the hydroxylated derivatives blocked the sodium channel in a voltage- and use-dependent manner. The PHM, HMM and NHM metabolites were up to 10-fold less effective than the parent compound. However, HMM showed a greater use-dependent behaviour (10 Hz), compared to Mex and the other metabolites. Similar to Mex, these products behaved as inactivating channel blockers. Conjugation with glucuronic acid (NMG) resulted in almost complete abolition of the pharmacological activity of the parent compound. CONCLUSIONS AND IMPLICATIONS: Thus, although less potent, the phase I metabolites tested demonstrated similar pharmacological behaviour to Mex and might contribute to its clinical profile.
Asunto(s)
Antiarrítmicos/metabolismo , Mexiletine/metabolismo , Músculo Esquelético/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Animales , Relación Dosis-Respuesta a Droga , Mexiletine/farmacología , Músculo Esquelético/metabolismo , Rana esculentaRESUMEN
Posterior Reversible Encephalopathy Syndrome (PRES) is a neurological complication associated with several medical conditions and it has been described in clinical findings of seizures, headache, vomiting, altered mental status, and visual changes and focal neurologic deficit, in conjunction with radiological findings of primarily posterior cerebral white matter edema of both cerebral hemispheres. PRES can develop in a wide array situations including pregnancy and postpartum in patients with or without symptoms and signs of eclampsia. A prompt diagnosis of PRES by magnetic resonance imaging and an immediate antihypertensive and anticonvulsant therapy can help to prevent serious complications. The clinical case presented deals with a 35 year-old pregnant woman whose history of eclampsia was observed after a cesarean section.
Asunto(s)
Eclampsia , Síndrome de Leucoencefalopatía Posterior/etiología , Adulto , Cesárea , Femenino , Humanos , Embarazo , Trastornos PuerperalesRESUMEN
The sea anemone toxin ATX II impairs skeletal muscle sodium channel inactivation, mimicking the persistent inward current observed in patients suffering from sodium channel myotonia. Mexiletine has beneficial effects on myotonia. To verify the efficiency of the drug on persistent inward current, we investigated the effect of 50 microM R(-)-mexiletine on sodium channels in cell-attached patches of rat skeletal muscle fibres, in the absence or presence of 2 microM ATX II. With the toxin, a proportion of channels displayed remarkable abnormal activity lasting the entire depolarisation, which resulted in a persistent inward current that represented up to 2.0% of the peak current. Mexiletine reduced by 75% the peak current elicited by depolarisation from -100 to -20 mV. This was due to the reduction by 60% of the maximal available peak current Imax and to the negative shift by -7 mV of steady-state inactivation. Mexiletine also greatly decreased the late current, but the effect was limited to 60% of reduction, comparable to that on Imax. Therefore mexiletine was able to block the ATX II-modified sodium channels, inhibiting the myotonia-producing persistent inward current.
Asunto(s)
Antiarrítmicos/farmacología , Venenos de Cnidarios/farmacología , Mexiletine/farmacología , Músculo Esquelético/efectos de los fármacos , Canales de Sodio/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/fisiología , Músculo Esquelético/fisiología , Miotonía/fisiopatología , Ratas , Canales de Sodio/fisiologíaRESUMEN
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.
Asunto(s)
Benzamidas/química , Dopaminérgicos/química , Piperazinas/química , Receptores de Dopamina D2/metabolismo , Animales , Benzamidas/metabolismo , Benzamidas/farmacología , Dopaminérgicos/metabolismo , Dopaminérgicos/farmacología , Cromatografía de Gases y Espectrometría de Masas , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Piperazinas/metabolismo , Piperazinas/farmacología , Ratas , Receptores de Dopamina D4 , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Benzamidas/síntesis química , Piperazinas/síntesis química , Receptores de Dopamina D2/metabolismo , Animales , Benzamidas/química , Benzamidas/metabolismo , Línea Celular , Corteza Cerebral/metabolismo , Humanos , Insectos , Ligandos , Piperazinas/química , Piperazinas/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptores de Dopamina D2/biosíntesis , Receptores de Dopamina D4 , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Piperazinas/química , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Tetrahidronaftalenos/química , Animales , Células CHO , Cricetinae , Cromatografía de Gases y Espectrometría de Masas , Humanos , Espectroscopía de Resonancia Magnética , Piperazinas/metabolismo , Ensayo de Unión Radioligante , Receptores de Serotonina 5-HT1 , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
2-(p-Chlorophenoxy)isobutyric acid (clofibric acid (1) or CPIB) is a drug known to block chloride membrane conductance (GCl) in rat striated muscle. In the present study chiral analogues of CPIB (2-(p-chlorophenoxy)propionic acid (2) and 2-(p-chlorophenoxy)butyric acid (3)) have been tested to evaluate the influence of chirality on Cl ion flux in the channel. The results showed that the chloride channel conductance strongly depends on the absolute configuration: in fact, the S-(-) isomers of the tested compounds strongly decreased the GCl of skeletal muscle membrane, whereas the R-(+) isomers were virtually ineffective. These data allow the hypothesis that, like other ion channels present in various biological systems, the chloride channel of skeletal muscle membrane could also have a stereospecific binding site (or receptor) regulating chloride ion flux.
Asunto(s)
Cloruros/metabolismo , Clofibrato/análogos & derivados , Ácido Clofíbrico/análogos & derivados , Canales Iónicos/efectos de los fármacos , Ácido 2-Metil-4-clorofenoxiacético/análogos & derivados , Ácido 2-Metil-4-clorofenoxiacético/farmacología , Animales , Membrana Celular/fisiología , Ácido Clofíbrico/farmacología , Canales Iónicos/fisiología , Masculino , Músculos/fisiología , Ratas , Ratas Endogámicas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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).
Asunto(s)
Piperidinas/química , Receptores sigma/metabolismo , Tetrahidronaftalenos/química , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ketanserina/metabolismo , Fenciclidina/metabolismo , Piperidinas/farmacología , Ratas , Receptores de Fenciclidina/metabolismo , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Espiperona/metabolismo , Relación Estructura-Actividad , Tetrahidronaftalenos/farmacologíaRESUMEN
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.
Asunto(s)
Dopaminérgicos/química , Oxígeno/química , Piperidinas/química , Animales , Encéfalo/metabolismo , Dopaminérgicos/metabolismo , Técnicas In Vitro , Ketanserina/metabolismo , Ratones , Piperidinas/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas , Receptores de Serotonina/metabolismo , Espiperona/metabolismoRESUMEN
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).
Asunto(s)
Piperidinas/química , Piperidinas/síntesis química , Receptores sigma/metabolismo , Tetrahidronaftalenos/química , Tetrahidronaftalenos/síntesis química , Animales , Encéfalo/metabolismo , Masculino , Piperidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/metabolismo , Receptor Sigma-1RESUMEN
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.
Asunto(s)
Piperazinas/metabolismo , Propilaminas/metabolismo , Receptores de Serotonina/metabolismo , Receptores sigma/metabolismo , Agonistas de Receptores de Serotonina/metabolismo , Tetrahidronaftalenos/metabolismo , Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cobayas , Espectroscopía de Resonancia Magnética , Masculino , Pentazocina/farmacología , Fenciclidina/metabolismo , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Propilaminas/síntesis química , Propilaminas/química , Propilaminas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Fenciclidina/metabolismo , Receptores de Serotonina 5-HT1 , Serotonina/metabolismo , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-Actividad , Tetrahidronaftalenos/síntesis química , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacologíaRESUMEN
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.
Asunto(s)
Piperazinas/síntesis química , Piperazinas/metabolismo , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/metabolismo , Animales , Buspirona/análogos & derivados , Buspirona/farmacología , Espectrometría de Masas , Estructura Molecular , Piperazinas/química , Piperazinas/farmacología , Unión Proteica , Ratas , Receptores Adrenérgicos/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina 5-HT1 , Serotonina/farmacología , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
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.