RESUMEN
3-Pyrrolidineacetic acid (1a), certain piperidinecarboxylic acids--i.e., 3-piperidinecarboxylic acid (2a), 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (3a), and cis-4-hydroxy-3-piperidinecarboxylic acid (4a)--cis-3-aminocyclohexanecarboxylic acid (5a, cis-3-ACHC), and gamma-aminobutyric acid (6a, GABA) itself are among the most potent inhibitors of [3H]GABA uptake by neurons and glia in vitro. These hydrophilic amino acids, however, do not readily enter the central nervous system in pharmacologically significant amounts following peripheral administration. We now report that N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (2b) is a specific GABA-uptake inhibitor that is more potent, more lipophilic and, in limited testing, as selective as 2a. Similar results were obtained with the N-(4,4-diphenyl-3-butenyl) derivatives of 1a, 3a, and 4a. By contrast, N-(4,4-diphenyl-3-butenyl) derivatives of 5a and 6a were not more potent than the parent amino acids and appear to inhibit GABA uptake, at least in part, by a nonselective mechanism of action. The N-(4,4-diphenyl-3-butenyl)amino acids 1b-4b exhibit anticonvulsant activity in rodents following oral or intraperitoneal administration [Yunger, L.M.; et al. J. Pharmacol. Exp. Ther. 1984, 228, 109].
Asunto(s)
Aminoácidos/síntesis química , Ácidos Carboxílicos/síntesis química , Inhibidores de la Captación de Neurotransmisores/síntesis química , Ácido gamma-Aminobutírico/fisiología , 4-Aminobutirato Transaminasa/metabolismo , Administración Oral , Alquilación , Aminoácidos/farmacología , Animales , Encéfalo/metabolismo , Ácidos Carboxílicos/farmacología , Glutamato Descarboxilasa/metabolismo , Técnicas In Vitro , Masculino , Inhibidores de la Captación de Neurotransmisores/administración & dosificación , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas , Receptores de GABA-A/metabolismo , Receptores de Neurotransmisores/metabolismo , Estereoisomerismo , Sinaptosomas/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Cerebral metabolic and vascular effects of hypothermia (30 C) and deep pentobarbital anesthesia, separately and combined, were evaluated in 15 mongrel dogs. External cardiovascular support was not used, and mean arterial blood pressures remained greater than 60 torr. Normothermic deep pentobarbital anesthesia, characterized by an electroencephalographic (EEG) frequency of less than 1 Hz, was associated with 30% decreases in cerebral metabolic rates for oxygen (CMRO2) and glucose (CMRG) from lightly anesthetized control values. Hypothermia (30 C) alone caused similar decreases in CMRO2 and CMRG in the presence of an active EEG. The use of pentobarbital anesthesia and hypothermia combined achieved significantly greater (P less than 0.05) decreases in CMRO2 (70%) and CMRG (72%) from the control state. Cerebral vascular resistance (CVR) increased by 70% (P less than 0.05) during hypothermia and about 20% when pentobarbital was administered to normothermic dogs. In hypothermic animals the addition of pentobarbital had a minimal effect on CVR. No alteration in the oxygen-glucose or lactate-glucose index indicative of cerebral hypoxia occurred in any experimental group. This study indicates that barbiturates combined with hypothermia decrease cerebral metabolism to a greater extent than hypothermia or barbiturate alone. When cerebral hypometabolism is therapeutically necessary, barbiturates may be indicated as an adjunct to moderate hypothermia.