1,721,157 research outputs found
Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors
No full textSeveral N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1,w-alkanediamine tetrahydrochlorides (1-7) were synthesized
and evaluated for their blocking activity on muscarinic receptors in guinea pig atria and rat ileum and bladder. The results were compared with those obtained for the classical nonselective muscarinic antagonist atropine. It was discovered that optimum activity is associated with an eight-carbon chain (compound 4) in guinea pig atria whereas, in both rat ileum and bladder, the 12-carbon analogue 7 had the highest activity. In addition, polymethylene tetraamines 1-6 displayed high selectivity toward guinea pig atria muscarinic receptors. The discriminatory power of 1-6 was not shared by 7. All the tetraamines were shown to be competitive antagonists of muscarinic receptors. N,N‘-bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine (4) was the most potent and selective toward muscarinic receptors in atria, with a pA2 value of 8.13 and a selectivity ratio (atria vs. ileum or bladder) of ca. 270. At a concentration of 10 microM, tetraamine 4 did not affect histamine and 5- hydroxytryptamine receptors of guinea pig ileum or alpha-adrenoreceptors of guinea pig atria whereas it inhibited postsynaptic alpha-adrenoreceptors of rat vas deferens with a -log K value of 5.23 and nicotinic receptors of frog rectus abdominis with an IC50 value of 0.23 microM. It is concluded that 4 is a novel, powerful, and selective tool in the characterization of muscarinic receptor subtypes
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
Further investigation on methoctramine-related tetraamines: Effects of terminal N-substitution and of chain length separating the four nitrogens on M2 muscarinic receptor blocking activity
No full textA series of tetraamines related to methoctramine (1) was synthesized and evaluated for its blocking activity on M2 and M3 muscarinic receptors of guinea pip left atria and ileum, respectively. Thus, tetraamines 2-7 were synthesized to evaluate the effect on affinity of replacing the 2-methoxybenzyl moiety of methoctramine by a phenethyl-type substituent. Furthermore, tetraamines 8 and 9 were investigated to analyze the effect on affinity of the chain length separating the inner nitrogens and the inner from outer nitrogens while keeping the total distance between the two outer nitrogens equal to that of methoctramine. It turned out that all the tetraamines investigated, although showing a significant affinity, were less active than methoctramine at M2 muscarinic receptors. The underlying drug-receptor interaction mechanisms are discussed
An improved synthesis of N,N'-bis[6-o-methoxyphenyl methyl hexylamino]1,8-octanediamine (methoctramine)
No full textAn improved synthesis of methoctramine as been reported
Molecular properties of the histamine H2-receptor. Covalent inhibition by tetraamine disulfides
No full textA series of tetraamine disulfides related to benextramine (an alpha-adrenoreceptor and H2-receptor antagonist) in which the distance between the inner and the outer nitrogens were changed from five to nine methylenes has been studied. Both effects of the displacement of the disulfide bridge by two methylenes and those of the progressive removal of two of the four nitrogens on the pharmacological profile have been assessed. Peak potency appeared to be associated with eight methylenes between the inner and the outer nitrogens and to four cationic charges as in the most active analogue 4 which was also investigated to assess its receptor specificity towards histamine H1 and muscarinic M2 and M3 receptors. The finding that the carbon analogue 11 (two methylenes for the disulfide bridge) was devoid of activity is consistent with the hypothesis that histamine H2-receptor inhibition is the result of a covalent bond formation by a way of a disulfide-thiol interchange reaction between the disulfide moiety of tetraamine disulfides and a receptor thiol group. However, the possibility that tetraamine disulfides may not act at the H2-receptor but beyond the receptor cannot be excluded
“Synthesis and α-Adrenoreceptor Blocking Properties of Phenoxybenzamine-Related (2-Chloroethyl)-(2,3-dihydrobenzo-[1,4] dioxin-2-ylmethyl)-(2-phenoxyethyl) Amines”.
No full textStructure-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
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