- A chemical switch for the modulation of the functional activity of higher homologues of histamine on the human histamine H3 receptor: Effect of various substitutions at the primary amino function
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In an effort to establish the structural requirements for agonism, neutral antagonism, and inverse agonism at the human histamine H3 receptor (H3R) we have prepared a series of higher homologues of histamine in which the terminal nitrogen of the side chain has been either mono- or disubstituted with several aliphatic, alicyclic, and aromatic moieties or incorporated in cyclic systems. The novel ligands have been pharmacologically investigated in vitro for their affinities on the human H3R and H4R subtypes by radioligand displacement experiments and for their intrinsic H3R activities via a CRE-mediated β-galactosidase reporter gene assay. Subtle changes of the substitution pattern at the side chain nitrogen alter enormously the pharmacological activity of the ligands, resulting in a series of compounds with a wide spectrum of pharmacological activities. Among the several neutral H3R antagonists identified within this series, compounds 2b and 2h display an H3R affinity in the low nanomolar concentration range (pKi values of 8.1 and 8.4, respectively). A very potent and selective H3R agonist (11, pEC 50 = 8.9, α = 0.94) and a very potent, though not highly selective, H3R inverse agonist (2k, pIC50 = 8.9, α = -0.97) have been identified as well.
- Govoni, Marinella,Lim, Herman D.,El-Atmioui, Dris,Menge, Wiro M. P. B.,Timmerman, Henk,Bakker, Remko A.,Leurs, Rob,De Esch, Iwan J. P.
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p. 2549 - 2557
(2007/10/03)
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- New high affinity H3 receptor agonists without a basic side chain
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In this study, we replaced the basic amine function of the known histamine H3 receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H3 receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H3 receptor over the human H4 receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H3 receptor agonist (pKi = 8.0 and pEC50 = 8.1) with a 320-fold selectivity at the human H3 receptor over the human H 4 receptor.
- Kitbunnadaj, Ruengwit,Hoffmann, Marcel,Fratantoni, Silvina A.,Bongers, Gerold,Bakker, Remko A.,Wieland, Kerstin,El Jilali, Ahmed,De Esch, Iwan J. P.,Menge, Wiro M. P. B.,Timmerman, Henk,Leurs, Rob
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p. 6309 - 6323
(2007/10/03)
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- ω-(Imidazol-4-yl)alkane-1-sulfonamides: a new series of potent histamine H3 receptor antagonists
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ω-(1H-Imidazol-4-yl)alkane-1-sulfonamides were prepared and found to be potent histamine H3 receptor antagonists. High receptor affinity and a low difference in the data between the bioassays were achieved with 5-(1H-imidazol-4-yl)pentane-1-sulfonic acid 4-chlorobenzylamide (16). Good in vitro profiles were also obtained for 2-hydroxysulfonamide and vinylsulfonamide analogues. This complements and completes the existing set of imidazole-based sulfonamides and sulfamides. Copyright
- Tozer, Matthew J.,Buck, Ildiko M.,Cooke, Tracey,Kalindjian,Pether, Michael J.,Steel, Katherine I.M.
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p. 425 - 432
(2007/10/03)
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- Fedrazole Hydrochloride: A Potent, Selective, Nonsteroidal Inhibitor ofAromatase for the Treatment of Estrogen-Dependent Disease
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A new class of potent, selective, nonsteroidal inhibitors of aromatase have been discovered.The most potent member of this series is fadrozole hydrochloride, CGS 16949 A, 4-(5,6,7,8-tetrahydroimidazopyridin-5-yl)benzonitrile monohydrochloride, 26a.
- Browne, L. J.,Gude, C.,Rodriguez, H.,Steele, R. E.
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p. 725 - 736
(2007/10/02)
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