Abstract
A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H(3)- and H(4)-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H(3)-receptor than the H(4)-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H(4)-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H(3)-receptor. As such, 3b and 3c are the first selective H(4) receptor agonists.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding, Competitive
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Cell Line
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Histamine Agonists / chemical synthesis*
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Histamine Agonists / chemistry
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Histamine Agonists / pharmacology
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Methylguanidine / analogs & derivatives
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Methylguanidine / chemical synthesis*
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Methylguanidine / chemistry
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Methylguanidine / pharmacology
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Receptors, G-Protein-Coupled*
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Receptors, Histamine / metabolism*
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Receptors, Histamine H3 / metabolism
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Receptors, Histamine H4
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Stereoisomerism
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Structure-Activity Relationship
Substances
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2-cyano-1-methyl-3-(5-(1H-imidazol-4(5)-yl)tetrahydrofuran-2-yl)methylguanidine
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HRH4 protein, human
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Histamine Agonists
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Imidazoles
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Receptors, G-Protein-Coupled
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Receptors, Histamine
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Receptors, Histamine H3
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Receptors, Histamine H4
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Methylguanidine