- 2-Aminoimidazole-based antagonists of the 5-HT6 receptor – A new concept in aminergic GPCR ligand design
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A new strategy in the design of aminergic GPCR ligands is proposed – the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT6R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT6R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a–z) exhibited high affinity for 5-HT6R and very high selectivity over 5-HT1A, 5-HT2A, 5-HT7 and D2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential.
- Hogendorf, Adam S.,Hogendorf, Agata,Kurczab, Rafa?,Kalinowska-T?u?cik, Justyna,Popik, Piotr,Nikiforuk, Agnieszka,Krawczyk, Martyna,Sata?a, Grzegorz,Lenda, Tomasz,Knutelska, Joanna,Bugno, Ryszard,Staroń, Jakub,Pietru?, Wojciech,Mat?oka, Miko?aj,Dubiel, Krzysztof,Moszczyński-P?tkowski, Rafa?,Pieczykolan, Jerzy,Wieczorek, Maciej,Pilarski, Bogus?aw,Zajdel, Pawe?,Bojarski, Andrzej J.
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supporting information
p. 1 - 15
(2019/06/24)
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- Substituted phenylacetylguanidines: a new class of antihypertensive agents
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The synthesis of a new series of phenylacetylguanidines is described. Several of them exhibited high antihypertensive activity in the rat. The most potent member of the series is N amidino 2 (2,6 dichlorophenyl) acetamide hydrochloride [2,6 dichlorophenylacetylguanidine hydrochloride, compound 19], which is now in clinical study under the clinical code number BS 100-141. The structure activity relationships in this class of compounds are discussed.
- Bream,Lauener,Picard,Scholtysik,White
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p. 1477 - 1482
(2007/10/05)
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