Studies on the structure-activity relationships of adrenergic beta-mimetic benzylamine derivatives. V. 9-Aryl-1H-2,3,7,8,9,10-hexahydrobenzo[d,e]quinolines.
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Biomedical subjects
Publications and source records attributed to Y Iwasawa.
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Plasma aspartate levels were measured after potassium aspartate administration through different routes to rats of various ages. The changes in plasma levels were most significant with intraperitoneal injection. Dose- and age-related responses to aspartate load were obtained. The present data suggest that a marked elevation of plasma aspartate levels may result in neuronal necrosis. By comparing the plasma aspartate levels with the results on hypothalamic lesion (Okaniwa et al., 1979), plasma peak value associated with the lesion was estimated in each case of various administration routes and rat ages.
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Appropriately substituted benzylamine (BZA) derivatives, fragmented derivatives of tetrahydroisoquinolines, were found to be directly acting adrenergic beta-stimulants, exhibiting tracheal relaxing, positive chronotropic and free fatty acid (FFA) releasing activities. The chemical structures essential for manifestation of the beta-action were i) 3,4-dihydroxybenzylamine, ii) arylmethyl group at position alpha, iii) lower alkyl group on the N atom. The structure activity relationships of BZA-derivatives were almost similar to, but partly different from those of tetrahydroisoquinoline- and catecholamine-derivatives. The tracheal relaxing, positive chronotropic and FFA-releasing actions of alpha-(3,4,5-trimethoxybenzyl)-N-methyl-3,4-dihydroxybenzylamine, the most active compound in the BZA-derivatives tested, were approximately one-hundred, thirty and fifty times less active than those of ISO, respectively. These results indicate that this compound is beta1-selective, while trimetoquinol is beta2-selective.
Curves of experimentally plotted log (dose ratio-1) vs.-log [B] for the antagonism between adrenergic beta-mimetics, isoproterenol (ISO) and trimetoquinol (TMQ), and various beta-antagonists in relaxation of guinea-pig trachea could not be reasonably fitted to Schild's equation which has been commonly used in the analysis of drug-antagonism. Taking into consideration the saturable uptake process of the drug used herein, the equation presented in this paper fitted fairly well to the experimental curves and explains the following results: 1, TMQ was more strongly antagonized than ISO by all the blocking agents tested, that is, the apparent modes of antagonism were different between ISO and TMQ although they are considered to interact with the same receptor site. 2, The slope of the curve for a given antagonist markedly differed between ISO and TMQ. It is hypothesized that ISO is more easily taken up than TMQ. This was experimentally confirmed: i.e., ISO was potentiated about 8 fold by inhibiting the uptake process with dibenamine while TMQ was not. By pretreatment with dibenamine, the log (dose ratio-1) vs.-log [B] curve for the ISO-propranolol antagonism was shifted upward and superimposed with the theoretical curve of antagonism in which uptake of the agonist was neglected.
In order to clarify whether or not trimetoquinol (TMQ) and isoproterenol (ISO) interact with the same receptor, the pA2 values of propranolol (PR) and certain trimethoxybenzene derivatives were measured, using isolated guinea pig tracheal chains. Each of PR, mescaline (MES) and its derivatives gave almost the same pA2 values for TMQ and ISO. Introduction of an alkyl group into the N atom of MES increased the affinity to the receptor in the order of methyl and isopropyl as well as the structureactivity relationship of catecholamines, while that of hydroxyl group in the beta-position of the side chain decreased pA2 values. The slopes of the regression lines for anti-TMQ action of MES derivatives as well as PR were almost one, but those for their anti-ISO action were less than 0.3. 3,4,5-Trimethoxyaniline and 3,4,5-trimethoxybenzoic acid had little activity as beta-blocking agents. These results suggest the possibility that TMQ and ISO would interact with the same receptor sites. The importance of the trimethoxybenzene and the phenethylamine moieties in the MES-derivatives for anti-TMQ action is discussed.
Studies were conducted on the participation of specific amino acids in the alterations of their levels in plasma and muscle of rats after short term intravenous infusion. Sufficient amounts of amino acids and glucose were used as a basal solution, and the levels in plasma and muscle were determined 30 min after the end of infusion. When an infusion solution devoid of one of the essential amino acids from the basal solution, -Leu, -Ile, -Lys or -Thr, was administered, the plasma and muscle levels of the deleted amino acids decreased in different degrees. With infusion of the deficient solutions except for the -Leu, no significant changes were observed in amino acids other than those deleted, although occasional changes were noted. On the other hand, the infusion of the -Leu resulted in significant increase of isoleucine and valine levels, and a moderate increase of many other amino acids both in plasma and in muscle. In contrast, when leucine was administered singly in an amount equivalent to that in the basal solution, isoleucine and valine decreased significantly. Most of the other amino acids also decreased markedly after the infusion of leucine alone. These results suggest that, in intravenous infusion, leucine plays a specific role on amino acid levels in plasma and muscle of rats.