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Molecular determinants of benzodiazepine receptor affinities and anticonvulsant activities 总被引:2,自引:0,他引:2
In vivo convulsant activities profiles and receptor binding studies together with the techniques of theoretical chemistry were used to characterize 15 compounds, from five different chemical families, known to bind to the BDZ receptor. The experimental goals of this study were to determine the affinity of these analogs for this receptor, the effect of gamma-aminobutyric acid on the affinity, and, in a self-consistent manner, the nature of the activity, agonist (anticonvulsant), antagonist, or inverse agonist (proconvulsant, convulsant), elicited by binding to this receptor. To these ends, in vivo studies were made to determine the proconvulsant, convulsant, and anticonvulsant activities and antagonism to anticonvulsant activities of the 15 analogs. Their receptor affinities at 25 degrees were also determined by competitive inhibition of [3H] flunitrazepam and [3H]Ro 15-1788 in the absence and presence of gamma-aminobutyric acid. The goal of the theoretical studies was to identify and calculate molecular properties that modulate these affinities and types of activities and from them to develop a model of receptor recognition and activation that could consistently explain observed behavior and predict new results. Thus, molecular orbital calculations were carried out for all analogs, using semiempirical quantum mechanical methods. In addition to the optimization of structures, a number of electronic properties, such as polarizations, partition coefficients, and proton and electron affinities were computed and examined for their ability to modulate relative affinities and modes of activation of the receptor. From these studies, a model for receptor recognition involving two anchoring hydrogen bond-acceptor sites and for activation involving interaction of the most lipophilic aromatic region of each compound with the receptor was developed, which could systematically account for the three different types of behavior, agonist, antagonist, and inverse agonist, observed for these analogs. Electronic rather than structural properties were found to be the principal modulator of both recognition and activation. A possible mechanism of agonist activation of the receptor involving electron transfer to the agonist, as well as a possible induced conformational change in the receptor, is also suggested by these results. Finally, by complementarity, some steric and electronic characteristics of the receptor binding site could be deduced. 相似文献
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As part of a broad study of the ocular and extraocular photoreceptors of reptiles, we have used high performance liquid chromatography (HPLC) to identify the retinoids present in whole eye extracts of the arboreal lizard Anolis carolinensis and the non-arboreal ruin lizard Podarcis sicula. Unexpectedly, only vitamin A2-derived chromophore was detected in Anolis, while a mixture of vitamin A1- and vitamin A2-derived chromophores was detected in Podarcis. These are the first examples of fully terrestrial vertebrates using vitamin A2-derived chromophore for visual pigment generation. Furthermore, microspectrophotometric (MSP) data for Anolis show a class of photoreceptor having a visual pigment with maximum absorbance at about 625 nm, some 40 nm further into the red than has been found in any terrestrial vertebrate examined to date. 相似文献
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F. Loew 《Acta neurochirurgica》1992,118(1-2):80-83
Summary Man is distinguished and differentiated from other living creatures by possessing less genetically determined characteristics, behaviour and reactions, with fewer features fitting him for a special environment. For this reason he enjoys greater freedom and adaptability.In order to be able to pass on the necessarry lessons for survival, man must have command of his speech, and as a species can only exist within communities. This presupposes an instinctive drive to make rules and regulations for ordered living in society.Speech is not only a means of communication but also the basis and precondition of abstract thinking. Complete aphasia implies the loss of this ability. It would deprive man from the most important of his key functions. Therefore it is inhuman.These reflections have convinced me absolutely, that neurosurgical interventions, which would have the predictable result of total aphasia, must not be performed, even though prolongation of life, but without speech, might thus be bought. 相似文献
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Ludwig Grepmair Ferdinand Mitterlehner Thomas Loew Marius Nickel 《European psychiatry》2007,22(8):485-489
This study examined whether the promotion of mindfulness in psychotherapists in training can influence the treatment results of their patients. The therapeutic course and treatment results of 196 inpatients, who were treated during a nine week period by nine psychotherapists in training, were compared: in the first phase of the study, the treatment group without (CG, historical control group, n=55), and in the second phase the treatment group with, (MFG, n=58) therapists who were currently practicing Zen meditation. The results of treatment were examined (according to the intent-to-treat principle) with the Session Questionnaire for General and Differential Individual Psychotherapy (STEP), the Questionnaire of Changes in Experience and Behaviour (VEV) and the Symptom Checklist (SCL-90-R), and showed significantly better results in the MFG. 相似文献