Synthesis and functional characterization of imbutamine analogs as histamine H3 and H4 receptor ligands.
Imbutamine (4-(1H-imidazol-4-yl)butanamine) is a potent histamine H3 (H3R) and H4 receptor (H4R) agonist (EC50 values: 3 and 66 nM, respectively). Aiming at improved selectivity for the H4R, the imidazole ring in imbutamine was methyl-substituted or replaced by various differently substituted heterocycles (1,2,3-triazoles, 1,2,4-triazoles, pyridines, pyrimidines) as potential bioisosteres. Investigations in [(35)S]GTPγS binding assays using membranes of Sf9 insect cells expressing the respective human histamine receptor subtype revealed only very weak activity of most of the synthesized hetarylalkylamines at both receptors. By contrast, the introduction of substituents at the 4-imidazolyl ring was most effective regarding H4R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5-Methylimbutamine (H4R: EC50  = 59 nM, α = 0.8) was equipotent with imbutamine at the hH4R, but revealed about 16-fold selectivity for the hH4R compared to the hH3R (EC50 980 nM, α = 0.36), whereas imbutamine preferred the hH3R. The functional activities were in agreement with radioligand binding data. The results support the hypothesis that, by analogy with histamine, methyl substitution in histamine homologs offers a way to shift the selectivity in favor of the H4R.
Faculty of Chemistry and Pharmacy, Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany.
Roland
R
Geyer
Melanie
M
Kaske
Paul
P
Baumeister
Armin
A
Buschauer
D000818:Animals; D002082:Butylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006632:Histamine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011968:Receptors, Histamine / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000074040:Receptors, Histamine H4; D061987:Sf9 Cells; D018411:Spodoptera; D013329:Structure-Activity Relationship; D014162:Transfection
C000589474:4-(1H-imidazol-4-yl)butanamine; D002082:Butylamines; C418607:HRH4 protein, human; D017442:Histamine Agonists; D007093:Imidazoles; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006632:Histamine
Bioisosteres; H3 receptor; H4 receptor; Histamine; Imbutamine