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Structure-Activity Relationships for Prazosin and WB4101 Analogues as alpha1-Adrenoreceptor Antagonist.
No full textSeveral a-adrenoreceptor antagonists were prepared by coupling one of the two moieties of WB 4101 (1) with oneof the two moieties of prazosin (2). Their blocking activity and relative selectivity on al- and a,-adrenoreceptorswere evaluated in the isolated rat vas deferens. Although retaining a significant selectivity toward al-adrenoreceptors,all the drugs were weaker antagonists than the parent compounds 1 and 2. Opening the piperazine ring of 2 gave3, which displayed a very high activity and selectivity toward a,-adrenoreceptors (a1/a2= 3890). This may haverelevance in understanding the mode of action of prazosin. In addition, 3 may represent a valuable tool in thecharacterization of a-adrenoreceptor subtypes
2-{[(2-(2,6-Dimethoxyphenoxy)ethyl]}-1,4-benzoxathiano:A New Antagonist With High Potency and Selectivity Toward alpha1-Adrenoreceptors.
No full textThese results emphasize the importance of the position 4 in both thebenzodioxan and benzoxathian nucleus for the interactionat a,-adrenoreceptors. Since sulfur cannot form a productivehydrogen bond, the position 4 of antagonists bearinga benzodioxan or a benzoxathian nucleus would interactwith the receptor, either increasing the electron densityof the phenyl ring by a way of an electron-releasing effector giving rise to a dipole-dipole interaction.In conclusion, compound 1 is a potent and selectivealpha1-adrenoreceptor antagonist that may represent a valuabletool in the characterization of a-adrenoreceptor subtypes
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 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 in 1,4-Benzodioxane Related Compounds. Investigation on the Role of the Dehydrodioxane Ring on alpha1-Adrenoreceptor Blocking Activity.
No full textSeveral analogues of 2 4 [ [2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-l,4-benzodiox(aWn B 4101, 1) were preparedand evaluated for their blocking activity on al- and az-adrenoreceptors in the isolated rat vas deferens. The resultswere compared with those obtained for 1 and benoxathian (2). It was shown that the two oxygens at positions 1and 4 may have a different role in receptor binding. It seems that the oxygen at position 4 as such does not contributeto the binding while it is important in stabilizing an optimal conformation for drug-receptor interaction mechanism.On the other hand, the oxygen at position 1 might interact with a receptor polar pocket of reduced size by way ofa donor-acceptor dipolar interaction. Furthermore, it was shown that replacement of the dehydrodioxane ring of1 by a phenyl or a pyrrole nucleus causes a significant decrease in activity
Structure-Activity Relationships Among Benextramine-Related Tetramine Disulfide at Peripheral Alpha-Adrenoreceptors.
No full textSeveral N,”’-(dithiodi-2,1-ethanediyl) bis~N’-(arylmethyl)-l,6-hexanediaminewse]r e prepared and evaluated fortheir blocking activity on postsynaptic al-adrenoreceptors in the isolated rat vas deferens. The results were comparedwith those obtained for benextramine (I). N~’~(Dithiodi-2,1-ethanediyl)bis[N’-(pyrrol-2-ylmethyl)-1,6-hexanediamine](pyrextramine, 29) was the most potent among the tetraamine disulfides investigated. Thus, it was selected forfurther pharmacological evaluation to assess its receptor specificity. At a concentration of 10 WM it did not affectthe responses elicited by 5-hydroxytryptamine and histamine in guinea pig ileum and by isoproterenol in guineapig atria and tracheal chain. Furthermore, it was more specific than benextramine (1) toward the muscarinic receptor,being significantly less potent in inhibiting the carbachol-induced response in rat jejunum. These results show thatpyrextramine (29) is an irreversible a-blocking agent that is more potent and specific than benextramine (I). Inconclusion, 29 may be a useful tool in the elucidation and characterization of the peripheral al-adrenoreceptor
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
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
(+)-Cyclazosin Derivatives as alpha1-Adrenoceptor Antagonists
No full textThe prazosin-related compound (+)-cyclazosin [(+)-1] is an α1-adrenoceptor antagonist with moderate selectivity for the α1b-adrenoceptor subtype (selectivity ratio: α1b/α1a 90, α1b/ α1d = 24). To improve its pharmacological profile, the novel chiral derivatives (+)-2-(+)-5, bearing a bromo, a methyl, a methoxy or an acetyl group in position 5 of the 2-furoyl moiety, were synthesized and evaluated for their α1b-adrenoceptor blocking activity. All the compounds displayed, like (+)-1, high and preferential affinity for the α1b-adrenoceptor in binding and functional assays. Interestingly, in functional assays, compounds (+)-3 and (+)-4 showed, in comparison with (+)-1, an increase in the α1B/α 1A selectivity (407 and 724 vs. 44), whereas compound (+)-5 exhibited an improved α1B/α1D selectivity
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