1,720,959 research outputs found
Fluoronorepinephrines: further pharmacological evaluation in vitro and inpithed rats
No full textThe effect of 6F-, 5F- and 2F-norepinephrine (6F-, 5F- and 2F-NE) in rat vas deferens, guinea-pig ileum and pithed rats was compared to that of norepinephrine (NE). The rank order of potency on postsynaptic alpha1-adrenoreceptors, determined from the isometric contraction of vas deferens, was 6F-NE = 5F-NE = NE > 2F-NE. A similar pattern was found for presynaptic alpha2-adrenoreceptor activity in both noradrenergic nerve terminals of vas deferens and cholinergic nerve terminals of the ileum, determined from the inhibition of contraction elicited by electrical field stimulation. The only exception was the 5F isomer which was 7 times less active than NE to activate the alpha2-adrenoreceptors of vas deferens. Thus, ring fluorination markedly alters both alpha1- and alpha2-agonist properties of NE. Moreover, selectivity, at least as far as rat vas deferens is concerned, is not significantly influenced by the introduction of a fluorine atom in the NE molecule. 6F-NE was about 3–4 times more active than NE in pithed rats. In turn, NE was equiactive with 5F-NE. 2F-NE was the least active isomer, being 30- and 100-fold less active than NE and 6F-NE, respectively
Structure-Activity Relationships in Prazosin-Related Compounds. Effect of Replacing a Piuperazine Ring with an Alkanediamine Moiety on alpa1-Adrenoreceptor Blocking Activity.
No full textSeveral prazosin-related compounds were synthesized in which the piperazine ring of prazosin (1) was replaced byan alkanediamine chain and were evaluated for their blocking activity on al- and a2-adrenoreceptors in isolatedrat vas deferens. All the compounds investigated proved highly selective toward the al-adrenoreceptor owing toa very low affinity for a2-adrenoreceptors. Furthermore, compounds 2,9, and 13 were also investigated in vivo todetermine their hypotensive effect on anesthetized rats, which were compared with that of prazosin (1). It was confirmedthat the piperazine moiety of 1 is not essential for potency. However, optimum activity depends on two parameters:carbon-chain length of the alkanediamine moiety and N-methylation of both the amide and the 2-amino functions.In the desmethyl series, optimum activity was associated with the lower homologues (2-4) bearing a chain of twoto four methylenes whereas in the N,N'-dimethyl series peak potency was observed with a six-carbon chain as in13. Compound 13 proved the most active of the series and was more potent than prazosin (1) in both in vivo andin vitro assays. It is hypothesized that the a,-adrenoreceptor incorporates a lipophilic area that is located betweenthe binding sites for the quinazoline and the furoyl moieties and is able to accommodate a polymethylene chain
Structure-activity relationships in prazosin-related compounds. Effect of replacing a piperazine ring with an alkanediamine moiety on alpha1- adrenoreceptorblocking activity.
No full textSeveral prazosin-related compounds were synthesized in which the piperazine ring of prazosin (1) was replaced by an alkanediamine chain and were evaluated for their blocking activity on alpha1- and alpha2-adrenoreceptors in isolated rat vas deferens. All the compounds investigated proved highly selective toward the alpha1-adrenoreceptor owing to a very low affinity for alpha2-adrenoreceptors. Furthermore, compounds 2,9, and 13 were also investigated in vivo to determine their hypotensive effect on anesthetized rats, which were compared with that of prazosin (1). It was confirmed that the piperazine moiety of 1 is not essential for potency. However, optimum activity depends on two parameters: carbon-chain length of the alkanediamine moiety and N-methylation of both the amide and the 2-amino functions. In the desmethyl series, optimum activity was associated with the lower homologues (2-4) bearing a chain of two to four methylenes whereas in the N,N'-dimethyl series peak potency was observed with a six-carbon chain as in 13. Compound 13 proved the most active of the series and was more potent than prazosin (1) in both in vivo and in vitro assays. It is hypothesized that the alpha1-adrenoreceptor incorporates a lipophilic area that is located between the binding sites for the quinazoline and the furoyl moieties and is able to accommodate a polymethylene chain
Structure-activity relationships among methoctramine-related polymethylene tetraamines. Chain-length and substituent effects on M2-muscarinic receptor blocking activity.
No full textSeveral polymethylene tetraamines related to methoctramine (1) were prepared and evaluated for their blocking activity on M-2 muscarinic receptors in guinea pig atria and ileum. It turned out that antimuscarinic potency depends on the following parameters: (a) nature of the substituent on both inner and outer nitrogens and (b) carbon chain length separating the inner nitrogens as well as the inner and outer nitrogens. Optimum activity at cardiac M-2 muscarinic receptors was associated with the chain lengths present in 1, that is, eight methylenes between the inner nitrogens and six methylenes between the inner and outer nitrogens. With regard to the substitueats, replacement of the benzylic moiety of 1 by a 2-fury1 or a 5-methyl-2-fury1 nucleus resulted in enhanced potency toward cardiac M-2 muscarinic receptors. In fact, furtramine (18) and mefurtramine (19) proved to be more potent and more selective than 1. Moreover, N-methylation of the four nitrogens of 1 gave different effects: methylation of the outer nitrogens, giving 22, caused a significant decrease in activity whereas methylation of the inner nitrogens, yielding 23, resulted in an increase in activity in both atria and ileum
Structure_Activity Relationships among Methoctramine-Related Polymethylene Tetramine. Chain Length and Substituent Effects on M2 Muscarinic Receptor Blocking Activity.
No full textSeveral polymethylene tetraamines related to methoctramine (1) were prepared and evaluated for their blockingactivity on M-2 muscarinic receptors in guinea pig atria and ileum. It turned out that antimuscarinic potency dependson the following parameters: (a) nature of the substituent on both inner and outer nitrogens and (b) carbon chainlength separating the inner nitrogens as well as the inner and outer nitrogens. Optimum activity at cardiac M-2muscarinic receptors was associated with the chain lengths present in 1, that is, eight methylenes between the innernitrogens and six methylenes between the inner and outer nitrogens. With regard to the substitueats, replacementof the benzylic moiety of 1 by a 2-fury1 or a 5-methyl-2-fury1 nucleus resulted in enhanced potency toward cardiacM-2 muscarinic receptors. In fact, furtramine (18) and mefurtramine (19) proved to be more potent and more selectivethan 1. Moreover, N-methylation of the four nitrogens of 1 gave different effects: methylation of the outer nitrogens,giving 22, caused a significant decrease in activity whereas methylation of the inner nitrogens, yielding 23, resultedin an increase in activity in both atria and ileum
Structure-Activity Relationships Among Benextramine Related Tetramine Disulfidxe. Chain Length Effect on alpha-adrenoreceptor Blocking Activity.
No full textSeveral N'-substituted N~"-(dithiodi-2,l-ethanediyl)bis(l,w-alkanediamines)w ere prepared and evaluated for theirblocking activity on a-adrenoreceptors in the isolated rat vas deferens and human blood platelets. The results werecompared with those obtained for benextramine (N,N"-(dithiodi-2,l-ethanediyl)bis[N'-[(2-methoxyphenyl)-methyl] - 1 ,g-hexanediamine], 10). Bendotramine (N,"'- (dithiodi-2,1 -ethanediyl) bis [ N'- [ (2-methoxypheny1)-methyl]-1,12-dodecanediamine]1,6 ) proved to be as active as 10 on al-adrenoreceptors, showing that optimum activityis associated with two carbon chain lengths separating inner from outer nitrogens of tetraamine disulfides. On theother hand, 16 had no activity up to 20 pM at a2-adrenoreceptors. The optimum activity at this receptor subtypewas associated with a six to eight carbon chain (10-12). Furthermore, 10 proved to be more selective towarda,-adrenoreceptors whereas 16 was a selective al-antagonist. The tetraamine disulfides were shown also to be potentinhibitors of human platelet aggregation induced by ADP or epinephrine. The potency increased with the carbonchain length. However, the results on platelets did not parallel those found in the rat vas deferens, indicating thatdifferences exist between the a-adrenoreceptor subtypes investigated. In conclusion, 10 may be a useful tool incharacterizing a,-adrenoreceptors whereas 16 might help in investigating a,-adrenoreceptors
Structure-activity relationships among benextramine-related tetraamine disulfides. Chain length effect on alpha-adrenoreceptor blocking activity1
No full textSeveral N'-substituted N,N"-(dithiodi-2,1-ethanediyl)bis(1,w-alkanediamines) were prepared and evaluated for their blocking activity on alpha-adrenoreceptors in the isolated rat vas deferens and human blood platelets. The results were compared with those obtained for benextramine (N,N"-(dithiodi-2,1-ethanediyl)bis[N'-[(2-methoxyphenyl)-methyl]-1,6-hexanediamine], 10). Bendotramine (N,N"-(dithiodi-2,1-ethanediyl)bis[N'-[(2-methoxyphenyl)-methyl]-1,12-dodecanediamine], 16) proved to be as active as 10 on alpha1-adrenoreceptors, showing that optimum activity is associated with two carbon chain lengths separating inner from outer nitrogens of tetraamine disulfides. On the other hand, 16 had no activity up to 20 microM at alpha2-adrenoreceptors. The optimum activity at this receptor subtype was associated with a six to eight carbon chain (10-12). Furthermore, 10 proved to be more selective toward alpha-adrenoreceptors whereas 16 was a selective alpha1-antagonist. The tetraamine disulfides were shown also to be potent inhibitors of human platelet aggregation induced by ADP or epinephrine. The potency increased with the carbon chain length. However, the results on platelets did not parallel those found in the rat vas deferens, indicating that differences exist between the alpha-adrenoreceptor subtypes investigated. In conclusion, 10 may be a useful tool in characterizing alpha2-adrenoreceptors whereas 16 might help in investigating alpha1-adrenoreceptors
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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