RESUMEN
A class of N-substituted tetrahydrobenzopyrano[3,4-c]pyridines, I, have been identified as antagonists of platelet activating factor (PAF). The structural features essential for PAF binding were determined by systematic modification of three sites in the molecule. While O-alkyl analogues had little effect on binding potency, N-alkyl analogues exhibited a wide range of activity. Structural changes in the core ring system generally resulted in a loss of binding activity. Optimization of the N- and O-substituents resulted in the analogues 25-27 which exhibited Ki values ranging between 131 and 167 nM in a [3H]PAF binding assay. Compound 23 was also active in a model of PAF-induced shock in the mouse following intravenous administration.
Asunto(s)
Benzopiranos/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Factor de Activación Plaquetaria/antagonistas & inhibidores , Glicoproteínas de Membrana Plaquetaria , Piridinas/síntesis química , Receptores Acoplados a Proteínas G , Alquilación , Animales , Benzopiranos/metabolismo , Benzopiranos/farmacología , Sitios de Unión , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Plaquetas/ultraestructura , Compuestos Bicíclicos con Puentes/farmacología , Membrana Celular/metabolismo , Gránulos Citoplasmáticos/efectos de los fármacos , Masculino , Ratones , Estructura Molecular , Factor de Activación Plaquetaria/metabolismo , Factor de Activación Plaquetaria/farmacología , Piridinas/farmacología , Conejos , Receptores de Superficie Celular/metabolismo , Choque/inducido químicamente , Relación Estructura-ActividadRESUMEN
(2RS,4R)-3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles represent a new class of potent, orally active antagonists of platelet activating factor (PAF). The compounds were prepared by acylation of the magnesium or zinc salts of substituted indoles with (2RS,4R)-2-(3-pyridinyl)-3-(tert-butoxycarbonyl)thiazolidin-4-oyl chloride. The 3-acylindole moiety functions as a hydrolytically stabilized and conformationally restricted anilide replacement, which imparts a considerable boost in potency to the series. Structure-activity relationships observed for substitution on the indole ring system are discussed. Members of the series compare favorably with other reported PAF antagonists.
Asunto(s)
Permeabilidad Capilar/efectos de los fármacos , Edema/tratamiento farmacológico , Indoles/farmacología , Factor de Activación Plaquetaria/antagonistas & inhibidores , Tiazoles/farmacología , Administración Oral , Animales , Edema/inducido químicamente , Técnicas In Vitro , Indoles/síntesis química , Indoles/química , Indoles/uso terapéutico , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Conejos , Ratas , Ratas Sprague-Dawley , Serotonina/sangre , Piel/efectos de los fármacos , Piel/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/uso terapéuticoRESUMEN
For the most part, those who have written on the ethics of complementary and alternative medicine (CAM) and integrative medicine have attempted simply to apply traditional bioethics (in the form of principles of autonomy, beneficence, nonmaleficence, and justice) to this new area of healthcare. In this article I argue that adopting the practices of CAM requires a new ethical understanding that incorporates the values implicit in those practices. The characteristics of CAM and conventional medicine can be translated into the language of healthcare values in a variety of ways. I suggest that they support 5 core values: integrated humanity, ecological integrity, naturalism, relationalism, and spiritualism. Characteristics of both CAM and conventional medicine are present in value. What is now thought of as principlism is, in this understanding, simply a subset within these values.
Asunto(s)
Bioética , Terapias Complementarias , Ética Médica , Humanos , Estados UnidosRESUMEN
PIP: This article is excerpted from the Park Ridge Center for the Study of Health, Faith, and Ethics 28-page handbook entitled "Religion and Public Discourse: Principles and Guidelines for Religious Participants." These principles are the product of a three-year research project conducted by the Center. The project "To Speak and Be Heard" is based upon a wide range of resources from within the participants' religious traditions, including practices, rituals, and tenets of faith. While this project grew out of the specific controversies around the Cairo Conference, the principles of civil discourse spelled out in this document are general in application and may be used to facilitate constructive public dialogue. This article also discusses the nature of civil discourse in the public square, covenants of conversation, engaging the other, living with conflict during and after conversation and argument, and the hope of civil discourse.^ieng