The #Rights4metoo Scale: a tool to monitor compliance with the convention on the rights of persons with disabilities / La escala #YoTambién Tengo Derechos: Una herramienta para monitorizar la convención sobre los derechos de las personas con discapacidad

There is a lack of psychometrically validated tools to evaluate the extent to which people with intellectual disability (ID) truly exercise their rights in all areas of their lives. The aim of this article is to provide evidence about the usefulness and reliability of the pilot version of the #Rights4MeToo Scale, an instrument based on the Quality of Life Supports Model. The scale can be self-reported by people with ID or hetero-reported by family members or professionals. First, through a qualitative study with self-advocates with ID, we provide evidence about the need and usefulness of this tool to understand and monitor compliance with the Convention on Rights of Persons with Disabilities (CRPD). Next, we present preliminary data on the internal consistency of the items that make up the pilot version, analyzing the responses of 1,200 people with ID, family members, and professionals. The #Rights4MeToo Scale will make it possible to conduct national studies on compliance with the CRPD, not to mention international comparative studies when the scale is adapted to the legal and cultural context of other countries. (AU)

Resulta urgente e ineludible contar con herramientas, con adecuadas evidencias de validez y fiabilidad, que permitan evaluar hasta qué punto las personas con discapacidad intelectual (DI) verdaderamente ejercen sus derechos en todos los ámbitos de su vida. El objetivo de este artículo consiste en proporcionar evidencias acerca de la utilidad y la fiabilidad de la versión preliminar de la escala #YoTambién Tengo Derechos, un instrumento diseñado a partir del Modelo de Calidad de Vida y Apoyos. La escala puede ser autoinformada por personas con DI o heteroinformada por familiares o profesionales. Por un lado, mediante un estudio cualitativo con autogestores con DI se proporcionan evidencias acerca de la necesidad y la utilidad de esta herramienta para conocer y monitorizar el cumplimiento de la Convención. Por otro lado, presentamos datos preliminares de la consistencia interna de los ítems, analizando las respuestas de 1.200 personas con DI, familiares y profesionales. La escala #YoTambién Tengo Derechos permitirá llevar a cabo estudios nacionales sobre el cumplimiento de la Convención sobre los Derechos de las Personas con Discapacidad y, con su adaptación al contexto legal y cultural de otros países, estudios comparativos internacionales. (AU)

Modelo esfuerzo-recompensa, salud y enfermedad en personal sanitario: una revisión sistemática / Effort-Reward Model and health and disease in healthcare workers: A systematic reviews

Scientific literature has shown relation between the perception of a high Effort-Reward Imbalance (ERI) and poor health or disease in healthcare workers. The aim of the study was to carry out a systematic review of how psychosocial risks in the work environment, conceptualized from the effort-reward imbalance model, influence different dimensions of health or illness in health care professionals. Articles that were published between 2010 and 2019 were reviewed by consulting Web of Knowledge, PsycINFO and Scopus databases. 27 scientific articles were included. High ERI and over-commitment are associated with poor health or disease in different dimensions.The main limitations of this review are a possible publication bias and the impossibility of establishing causal relationships between environmental psychosocial risks and health or illness. It is necessary to address the psychosocial risks of the health care work environment and to implement improvement programs to achieve a good balance between efforts and rewards.

La bibliografía científica ha evidenciado asociaciones entre la percepción de un alto desequilibrio esfuerzo-recompensa (Effort-Reward Imbalance, ERI) y mala salud o enfermedad en sanitarios. En este trabajo se realizó una revisión sistemática de estudios que analizaron cómo influyen los riesgos psicosociales del entorno laboral, conceptualizados desde el modelo del desequilibrio esfuerzo-recompensa, en diferentes dimensiones de salud o enfermedad en personal sanitario. Para ello, se revisaron artículos publicados entre 2010 y 2019 consultando las bases de datos Web of Knowledge, PsycINFO y Scopus. Se incluyeron 27 artículos científicos. Un alto ERI y un exceso de compromiso (sobrecompromiso) se asocian con mala salud o enfermedad en personal sanitario. Las principales limitaciones de esta revisión son un posible sesgo de publicación y la imposibilidad de establecer relaciones de causalidad entre los riesgos psicosociales del entorno y la salud o enfermedad. Es necesario evaluar los riesgos psicosociales del entorno laboral de los sanitarios y desarrollar y aplicar programas de intervención para que haya un ajuste adecuado entre esfuerzos y recompensas.

Combined therapy of ruthenium dendrimers and anti-cancer drugs against human leukemic cells.

Carbosilane ruthenium(ii) dendrimers have been complexed with conventional anti-cancer drugs. Due to its features, the presence of ruthenium within a dendrimer structure improves the anti-cancer properties of nanocomplexes containing 5-flurouracyl, methotrexate and doxorubicin. These dendrimers could be promising carriers of anti-cancer medicines. Ruthenium dendrimers that are positively charged can also enhance the cytotoxicity to cancer cells; moreover, they can form stable complexes with drugs. Results indicate that ruthenium dendrimers combined with doxorubicin and methotrexate significantly reduced the viability of leukaemia 1301 and HL-60 cancer cells.

Cultura de seguridad del paciente en la formación de enfermería / Patient Safety Culture in Nursing Training

Introducción: La cultura de seguridad del paciente es el conjunto de creencias, valores, costumbres, percepciones, normas, competencias y prácticas presentes en el clima organizacional de los profesionales de salud, lo cual se refleja en las acciones proactivas o reactivas de seguridad clínica. Objetivo: Describir la cultura de seguridad del paciente en los estudiantes durante la formación técnica en enfermería. Métodos: Transversal y descriptivo. El cuestionario se administró a 113 estudiantes; igualmente se aplicó una guía de observación directa a 26 estudiantes durante el desarrollo de las prácticas de aprendizaje de enfermería en las simulaciones de atención a pacientes. Ambos instrumentos abordaron las principales dimensiones de la cultura de seguridad clínica. Resultados: El 85,84 por ciento fueron mujeres, la media de edad fue de 22,3 años, con una desviación típica de 4,156; el mayor porcentaje se ubicó en el grupo de 21 a 25 años con un 40,71 por ciento. Los resultados sobre el conocimiento en seguridad del paciente fue que el 80,53 por ciento tenía una percepción positiva sobre el error, el 57,52 por ciento no definió si era necesario hablar de errores, el 71,68 por ciento involucró el factor humano en el error y el 66,37 por ciento consideró importante involucrar a los pacientes. La valoración de la práctica evidenció que 85,84 por ciento no identifica al paciente, mientras que 100 por ciento de los estudiantes no perciben una respuesta punitiva ante errores en la evaluación de su práctica simulada. Conclusiones: La cultura de seguridad es un conocimiento teórico para los estudiantes de enfermería y debe fortalecerse como competencia a nivel curricular(AU)

Introduction: A culture of patient safety is the set of beliefs, values, customs, perceptions, norms, competencies, and practices present in the organizational climate of health professionals, a fact reflected in the proactive or reactive actions of clinical safety. Objective: To describe the culture of patient safety in students during technical nursing training. Methods: Cross-sectional and descriptive. The questionnaire was applied to 113 students. A direct-observation guide was also applied to 26 students during the development of nursing learning practices in patient care simulations. Both instruments addressed the main dimensions of clinical safety culture. Results: 85.84 percent were women. The mean age was 22.3 years, with a standard deviation of 4.156. The highest percentage was in the group of 21 to 25 years of age, accounting for 40.71 percent. Regarding the results related to knowledge about patient safety, 80.53 percent had a positive error perception, 57.52 percent did not define whether it was necessary to talk about errors, 71.68 percent involved the human factor in error, and 66.37 percent considered it important to involve patients. The evaluation of performance showed that 85.84 percent did not identify the patient, while 100 percent of the students did not perceive a punitive response to errors in the evaluation of their simulated performance. Conclusions: Safety culture is theoretical knowledge for nursing students and should be strengthened as a competency at the curricular level(AU)

Versatile Route to trans-Platinum(II) Complexes via Manipulation of a Coordinated 3-(Pyridin-3-yl)propanoic Acid Ligand.

We describe the direct coupling of alcohols and amines to a 3-(pyridin-3-yl)propanoic acid ligand coordinated to a Pt(II) to afford ester and amide derivatives. Using this approach, a family of trans-Pt(II) compounds with amine ligands bearing long perfluorinated chains was prepared, as these chains potentially endow the complexes with thermoactivatable properties. Related compounds with alkyl chains in place of the perfluorinated chains were also prepared as controls using the same direct coupling method. The stability of the complexes in solution, their reactivity with DNA and proteins, and their antiproliferative activity evaluated in tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK293) cells at 37 °C and following exposure to elevated temperatures (that mimic the temperatures employed in thermotherapy) were also studied to assess their utility as putative (thermoactivated) anticancer agents.

[To promote knowledge on patient safety: the case of the Biblioteca Breve de Seguridad del Paciente (Brief Patient Safety Library)]. / Para avanzar en el conocimiento de la seguridad del paciente: a propósito de la biblioteca breve de seguridad del paciente.

OBJECTIVE: Within the framework of the Patient Safety Strategy 2015-2020, the Regional Ministry of Health of the Community of Madrid developed two lines of action to consolidate the Patient Safety Culture through the dissemination of scientific knowledge in Patient Safety. The main objective was to identify, disseminate and improve access to relevant information on patient safety for patient-citizens, professionals and the organization itself through a pool of resources accessible on the Internet and intranet. METHODS: After an analysis of the tools and communication channels available to disseminate knowledge in patient safety, the references of interest were selected by a group of experts, a consultation tool was developed in a navigable format on the internet and various dissemination actions were carried out to make it known. RESULTS: The Biblioteca Breve de Seguridad del Paciente (Brief Patient Safety Library) was developed, accessible for navigation on the web of the Community of Madrid and as a download document, with 154 references, structured in 4 areas: General resources (74 references), Resources by thematic area (51 references), Videos and multimedia (12 references) and Organizations and websites of interest (17 references). CONCLUSIONS: The Biblioteca Breve de Seguridad del Paciente (Brief Patient Safety Library) can help to promote the safety culture in health centers and to achieve greater citizen involvement in their safety, by providing reliable information on this crosscutting dimension of clinical practice.

OBJETIVO: En el marco de la Estrategia de Seguridad del Paciente 2015-2020 la Consejería de Sanidad de la Comunidad de Madrid desarrolló dos líneas de actuación para consolidar la cultura de seguridad a través de la difusión del conocimiento científico en Seguridad del Paciente. El objetivo principal fue identificar, difundir y mejorar el acceso a la información relevante en seguridad del paciente a pacientes-ciudadanos, profesionales y a la propia organización mediante un catálogo de recursos accesible en internet e intranet. METODOS: Tras un análisis de las herramientas y canales de comunicación disponibles para difundir el conocimiento en seguridad del paciente, se seleccionaron las referencias de interés por un grupo de expertos, se desarrolló una herramienta de consulta en un formato navegable en internet y se realizaron distintas acciones de difusión para darla a conocer. RESULTADOS: Se desarrolló la Biblioteca Breve de Seguridad del Paciente, accesible en la web de la Comunidad de Madrid para navegación y como documento para descargar, con 154 referencias, estructuradas en 4 áreas: Recursos generales (74 referencias), Recursos por Área temática (51 referencias), Videos y multimedia (12 referencias) y Organismos y sitios web de interés (17 referencias). CONCLUSIONES: La Biblioteca Breve de Seguridad del Paciente puede contribuir a impulsar la cultura de seguridad en los centros sanitarios y a lograr mayor implicación de los ciudadanos en su seguridad, al poner a su disposición información fiable sobre esta dimensión transversal de la práctica clínica.

[Medication administration errors at an emergency service: knowing to decrease risk]. / Errores en la administración de medicación en un servicio de urgencias: conocer para disminuir el riesgo.

OBJECTIVE: TThere is a great potential risk of errors in the emergency services and the studies carried out present heterogeneous results and methodology. The aim was to calculate the prevalence and characteristics, types and consequences for the patient, of medications administration errors in patients who attended the emergency department (ED) of a tertiary hospital, and to propose improvement strategies to prevent them. METHODS: A cross-sectional study of direct observation in the emergency areas of internal medicine and observation of adult patients was conducted in September 2016. Data collection was conducted by 4, nursing professional's observers from the ED. Medication errors reported by professionals to the hospital's voluntary reporting system were also analysed. RESULTS: The number of medication administration errors observed was 150 (19%) versus the number of medication administration errors reported to the hospital's notification system, which was 14, from 2013 to 2016. The most frequent type of error was incorrect administration rate (67%), followed by preparation errors (16%) and incorrect time administration (14%). The medications that accumulated the most errors were furosemide and methylprednisolone. None of the errors involved damage to the patient. Descriptive statistics was used to summarize the results of the study. CONCLUSIONS: The prevalence of medication administration errors in the ED is high. Knowing about them is effective to undertake specific improvement actions that may influence prevention, increasing patient safety.

OBJETIVO: Existe un gran riesgo potencial de errores en los servicios de urgencias y los estudios realizados presentan resultados y metodología heterogénea. El objetivo de este trabajo fue calcular la prevalencia y características de los errores, tipos y consecuencias para el paciente, relacionados con la administración de medicamentos a pacientes atendidos en el servicio de urgencias (SU) de un hospital de tercer nivel, así como proponer estrategias de mejora que puedan prevenirlos. METODOS: Estudio transversal, de observación directa realizado en las áreas de urgencias de medicina interna y observación de pacientes adultos, en el mes de septiembre de 2016. La recogida de datos se realizó por un total de 4 observadores, profesionales de enfermería del SU. También se recogieron los errores de medicación reportados por los profesionales al sistema de notificación voluntario del centro. Se utilizó estadística descriptiva para resumir los resultados del estudio. RESULTADOS: El número de errores de administración de la medicación observada fue de 150 (19%) frente al número de errores de administración de la medicación reportados al sistema de notificación del centro que fue de 14, en el periodo de 2013 a 2016. El tipo de error más frecuente fue la velocidad de administración incorrecta (67%), seguido de los errores de preparación (16%) y el de frecuencia de administración incorrecta (14%). Los medicamentos que más errores acumularon fueron la furosemida y la metilprednisolona. Ninguno de los errores supuso un daño para el paciente. CONCLUSIONES: La prevalencia de errores de administración de la medicación en el SU es elevada. Conocerlos es eficaz para emprender acciones de mejora específicas que puedan influir en su prevención, aumentando la seguridad del paciente.

Errores en la administración de medicación en un servicio de urgencias: conocer para disminuir el riesgo / Medication administration errors at an emergency service: knowing to decrease risk

Fundamentos: Existe un gran riesgo potencial de errores en los servicios de urgencias y los estudios realizados presentan resultados y metodología heterogénea. El objetivo de este trabajo fue calcular la prevalencia y características de los errores, tipos y consecuencias para el paciente, relacionados con la administración de medicamentos a pacientes atendidos en el servicio de urgencias (SU) de un hospital de tercer nivel, así como proponer estrategias de mejora que puedan prevenirlos. Métodos: Estudio transversal, de observación directa realizado en las áreas de urgencias de medicina interna y observación de pacientes adultos, en el mes de septiembre de 2016. La recogida de datos se realizó por un total de 4 observadores, profesionales de enfermería del SU. También se recogieron los errores de medicación reportados por los profesionales al sistema de notificación voluntario del centro. Se utilizó estadística descriptiva para resumir los resultados del estudio. Resultados: El número de errores de administración de la medicación observada fue de 150 (19%) frente al número de errores de administración de la medicación reportados al sistema de notificación del centro que fue de 14, en el periodo de 2013 a 2016. El tipo de error más frecuente fue la velocidad de administración incorrecta (67%), seguido de los errores de preparación (16%) y el de frecuencia de administración incorrecta (14%). Los medicamentos que más errores acumularon fueron la furosemida y la metilprednisolona. Ninguno de los errores supuso un daño para el paciente. Conclusiones: La prevalencia de errores de administración de la medicación en el SU es elevada. Conocerlos es eficaz para emprender acciones de mejora específicas que puedan influir en su prevención, aumentando la seguridad del paciente

Background: There is a great potential risk of errors in the emergency services and the studies carried out present heterogeneous results and methodology. The aim was to calculate the prevalence and characteristics, types and consequences for the patient, of medications administration errors in patients who attended the emergency department (ED) of a tertiary hospital, and to propose improvement strategies to prevent them. Methods: A cross-sectional study of direct observation in the emergency areas of internal medicine and observation of adult patients was conducted in September 2016. Data collection was conducted by 4, nursing professional's observers from the ED. Medication errors reported by professionals to the hospital's voluntary reporting system were also analysed. Results: The number of medication administration errors observed was 150 (19%) versus the number of medication administration errors reported to the hospital's notification system, which was 14, from 2013 to 2016. The most frequent type of error was incorrect administration rate (67%), followed by preparation errors (16%) and incorrect time administration (14%). The medications that accumulated the most errors were furosemide and methylprednisolone. None of the errors involved damage to the patient. Descriptive statistics was used to summarize the results of the study. Conclusions: The prevalence of medication administration errors in the ED is high. Knowing about them is effective to undertake specific improvement actions that may influence prevention, increasing patient safety

La Educación para la Salud y la continuidadde los cuidados al alta hospitalaria de una Unidad de Medicina Interna. Opinión de pacientes y cuidadores / Health Education and the continuity of care at discharge from an Internal Medicine Unit. Opinion of patients and carers

Objetivo: valorar la opinión de los pacientes y/o cuidadores ingresadosen una unidad de medicina interna, sobre el materialeducativo elaborado para una actividad de Educación parala Salud (EPS), dirigido a las necesidades de cuidado alteradasal alta hospitalaria.Material y métodos: estudio descriptivo transversal realizadoen el Hospital Príncipe de Asturias de Madrid, con 156 pacientesingresados en una unidad de medicina interna que presentabanun nivel de dependencia moderado-leve. Las variables delestudio: edad, sexo, presencia de cuidadores, grado de dependenciamedido por la Escala de Incapacidad Física de la Cruz Roja,motivo clínico de ingreso y opinión sobre los folletos utilizadosdirigidos a las necesidades alteradas. Además del uso de fuentesdocumentales se aplicó un cuestionario de elaboración propia.Resultados: el 76% de los pacientes del estudio tenían cuidadoresen el domicilio y el grado de dependencia 1 (leve) fueel más frecuente (52%). Las necesidades básicas que más precisaronde EPS apoyada por los folletos fue la de alimentación(95,2%), evitar peligros (81%) y la de movilidad (61,9%).En la valoración de la opinión de pacientes y/o cuidadores sobreel material escrito entregado, se encontró que un 85,7% losentendía muy bien y el 85,8% lo consideraba muy útil. Sóloel 37,8% concedió el valor máximo a la posibilidad de ejecuciónde las medidas en el domicilio.Conclusiones: la introducción de folletos con medidas higiénico-dietéticas para el manejo de las necesidades básicas alteradasfue recibida por pacientes y/o cuidadores de forma positiva.Los folletos proporcionan información sencilla y útilsobre medidas que pueden incidir en la independencia de lospacientes al alta hospitalaria. Es necesario realizar más estudiosque valoren su impacto real en el momento del alta ytiempo después en el domicilio (AU)

Objective: to assess the opinion of patients and/or carers admittedto an internal medicine unit, on the educational materialdeveloped for a Health Education activity aimed at addressingaltered care needs at hospital discharge.Material and methods: cross-sectional descriptive study performedin the Príncipe de Asturias Hospital of Madrid, with156 patients admitted to an internal medicine unit who presenteda moderate-mild level of dependence. Study variableswere: age, sex, presence of carers, level of dependence measuredusing the Cruz Roja’s Physical Incapacity Scale, clinical reasonfor admittance and opinion on the leaflets used aimed ataddressing altered needs. In addition to the use of documentalsources, a self-elaborated questionnaire was administered.Results: 76% of patients in the study had carers in their homeand the most frequent level of dependence was 1 (mild) (52%).The basic needs that most required leaflet-supported healtheducation were diet (95,2%), avoidance of danger (81%) andmobility (61,9%). In the assessment of the opinion of patientsand/or carers on the written material that was provided, 85,7%understood the information very well and 85,5% deemed it tobe very useful. Only 37,8% assigned the maximum value tothe possibility of performing these measures at home.Conclusions: the use of leaflets presenting hygienic-dietary measuresfor the management of altered basic needs was positivelyreceived by patients and/or carers. The leaflets providedsimple and useful information on the measures that can affectthe patient’s independence at hospital discharge. Further studiesshould be carried out to assess their real impact at dischargeand in the following period of time at home (AU)

Development of an HTS assay for the search of anti-influenza agents targeting the interaction of viral RNA with the NS1 protein.

The NS1 protein is a nonstructural protein encoded by the influenza A virus. It is responsible for many alterations produced in the cellular metabolism upon infection by the virus and for modulation of virus virulence. The NS1 protein is able to perform a large variety of functions due to its ability to bind various types of RNA molecules, from both viral and nonviral origin, and to interact with several cell factors. With the aim of exploring whether the binding of NS1 protein to viral RNA (vRNA) could constitute a novel target for the search of anti-influenza drugs, a filter-binding assay measuring the specific interaction between the recombinant His-NS1 protein from influenza A virus and a radiolabeled model vRNA ( 32P-vNSZ) was adapted to a format suitable for screening and easy automation. Flashplate technology (PerkinElmer, Waltham, MA), either in 96- or 384-well plates, was used. The Flashplate wells were precoated with the recombinant His-NS1 protein, and the binding of His-NS1 to a 35S-vNSZ probe was measured. A pilot screening of a collection of 27,520 mixtures of synthetic chemical compounds was run for inhibitors of NS1 binding to vRNA. We found 3 compounds in which the inhibition of NS1 binding to vRNA, observed at submicromolar concentrations, was correlated with a reduction of the cytopathic effect during the infection of cell cultures with influenza virus. These results support the hypothesis that the binding of NS1 to vRNA could be a novel target for the development of anti-influenza drugs.

Cyclic analogs of alpha-melanocyte-stimulating hormone (alphaMSH) with high agonist potency and selectivity at human melanocortin receptor 1b.

Alpha-melanotropin (alphaMSH), Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2,(1) has been long recognized as an important physiological regulator of skin and hair pigmentation in mammals. Binding of this peptide to the melanocortin receptor 1 (MC1R) leads to activation of tyrosinase, the key enzyme of the melanin biosynthesis pathway. In this study, interactions of the human MC1bR (an isoform of the receptor 1a) with the synthetic cyclic analogs of alphaMSH were studied. These ligands were analogs of MTII, Ac-Nle4-cyclo-(Asp5-His6-D-Phe7-Arg8-Trp9-Lys10)-NH2, a potent pan-agonist at the human melanocortin receptors (hMC1,3-5R). In the structure of MTII, the His6-D-Phe7-Arg8-Trp9 segment has been recognized as "essential" for molecular recognition at the human melanocortin receptors (hMC1,3-5R). Herein, the role of the Trp9 in the ligand interactions with the hMC1b,3-5R has been reevaluated. Analogs with various amino acids in place of Trp9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4 and 5 (hMC1b,3-5R). Several of the new peptides were high potency agonists (partial) at hMC1bR (EC50 from 0.5 to 20 nM) and largely inactive at hMC3-5R. The bulky aromatic side chain in position 9, such as that in Trp, was found not to be essential to agonism (partial) of the studied peptides at hMC1bR.

Analogs of alpha-melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: the role of Trp(9) in molecular recognition.

alpha-Melanocyte stimulating hormone (alphaMSH), Ac-Ser(1)-Tyr(2)-Ser(3)-Met(4)-Glu(5)-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH(2), is an endogenous agonist for the melanocortin receptor 1 (MC1R), the receptor found in the skin, several types of immune cells, and other peripheral sites. Three-dimensional models of complexes of this receptor with alphaMSH and its synthetic analog NDP-alphaMSH, Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-D-Phe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH(2), have been previously proposed. In those models, the 6-9 segment of the ligand was considered essential for the ligand-receptor interactions. In this study, we probed the role of Trp(9) of NDP-alphaMSH in interactions with hMC1bR. Analogs of NDP-alphaMSH with various amino acids in place of Trp(9) were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4, and 5 (hMC1b,3-5R). Several new compounds displayed high agonist potency at hMC1bR (EC(50) = 0.5-5 nM) and receptor subtype selectivity greater than 2000-fold versus hMC3-5R. The Trp(9) residue of NDP-alphaMSH was determined to be not essential for molecular recognition at hMC1bR.

Melanocortin subtype 4 receptor agonists: structure-activity relationships about the 4-alkyl piperidine core.

SAR about the piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported.

Potent and selective peptide agonists of alpha-melanocyte stimulating hormone (alphaMSH) action at human melanocortin receptor 5; their synthesis and biological evaluation in vitro.

Melanocortin receptors (MC1-5R) and their endogenous ligands (melanocyte-stimulating hormones and adrenocorticotropic hormone) are involved in many physiological processes in humans. Of those receptors, the actions of MC5R are the least understood despite its broad presence in the numerous peripheral tissues and brain. In this study, we describe synthesis and pharmacological properties in vitro (receptor-binding affinity and agonist activity) of several cyclic analogs of alphaMSH which are potent agonists at hMC5R (EC(50) below 1 nM) and of enhanced receptor subtype selectivity (more than 2000-fold versus hMC1b,3R and about 70- to 200-fold versus hMC4R). These compounds are analogs of Ac-Nle(4)-cyclo[Asp(5)-His(6)-D-Nal(2')(7)-Pip(8)-Trp(9)-Lys(10)]-NH(2) (Pip: pipecolic acid) in which His(6) has been replaced with sterically hindered amino acids. They may be useful tools in the elucidation of the MC5R role in skin disorders and in immunomodulatory and in anti-inflammatory actions of alphaMSH.

Potent and selective agonists of human melanocortin receptor 5: cyclic analogues of alpha-melanocyte-stimulating hormone.

The physiological role of melanocortin receptor 5 (MC5R) in humans is not clear despite its broad presence in various peripheral sites and in the brain, cortex, and cerebellum. To differentiate between functions of this receptor and those of the other melanocortin receptors (hMC1,3,4R), peptides with improved receptor subtype selectivity are needed. The endogenous ligands, melanocortins, and their various synthetic analogues are not particularly selective for hMC5R. In this study, cyclic peptides derived from MTII, Ac-Nle-cyclo(Asp-His6-D-Phe7-Arg8-Trp-Lys)-NH2 (a pan-agonist at the melanocortin receptors) were prepared and tested in binding and functional assays on CHO cells expressing hMC1b,3-5R. The analogues included in their structures sterically constrained hydrophobic amino acids in positions 6 (His) and 8 (Arg), and the D-4,4'-biphenyl residue in position 7 (D-Phe). Several of the new compounds were selective potent agonists at hMC5R. They are exemplified by peptide 29, Ac-Nle-cyclo(Asp-Oic6-D-4,4'-Bip7-Pip8-Trp-Lys)-NH2 (Oic=octahydroindole-2-COOH; 4,4'-Bip=4,4'-biphenylalanine; Pip=pipecolic acid) of IC50=0.95 nM and EC50=0.99 nM at hMC5R and selectivity for this receptor with respect to the other melanocortin receptors greater than 5000-fold.

Potent and selective agonists of alpha-melanotropin (alphaMSH) action at human melanocortin receptor 5; linear analogs of alpha-melanotropin.

Alpha-melanotropin, Ac-Ser(1)-Tyr-Ser-Met-Glu-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2)(1), is a non-selective endogenous agonist for the melanocortin receptor 5; the receptor present in various peripheral tissues and in the brain, cortex and cerebellum. Most of the synthetic analogs of alphaMSH, including a broadly used and more potent the NDP-alphaMSH peptide, Ac-Ser(1)-Tyr-Ser-Nle(4)-Glu-His(6)-D-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2), are also not particularly selective for MC5R. To elucidate physiological functions of the melanocortin receptor 5 in rodents and humans, the receptor subtype selective research tools are needed. We report herein syntheses and pharmacological evaluation in vitro of several analogs of NDP-alphaMSH which are highly potent and specific agonists for the human MC5R. The new linear peptides, of structures and solubility properties similar to those of the endogenous ligand alphaMSH, are exemplified by compound 7, Ac-Ser(1)-Tyr-Ser-Met-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2) (Oic: octahydroindole-2-COOH, 4,4'-Bip: 4,4'-biphenylalanine, Pip: pipecolic acid), shortly NODBP-alphaMSH, which has an IC(50)=0.74 nM (binding assay) and EC(50)=0.41 (cAMP production assay) at hMC5R nM and greater than 3500-fold selectivity with respect to the melanocortin receptors 1b, 3 and 4. A shorter peptide derived from NODBP-alphaMSH: Ac-Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9) -NH(2) (17) was measured to be an agonist only 10-fold less potent at hMC5R than the full length parent peptide. In the structure of this smaller analog, the Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8) segment was found to be critical for high agonist potency, while the C-terminal Trp(9) residue was shown to be required for high hMC5R selectivity versus hMC1b,3,4R.

Identification and optimisation of 5-amino-7-aryldihydro-1,4-diazepines as 5-HT2A ligands.

A several series of low molecular weight 5-HT(2A) leads were identified from an analysis of HTS data, the exploration of SAR and optimization of one series using parallel synthesis are described, affording compound 22 (5-HT(2A) IC(50) 1.1 nM).