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Synthesis and Functional Characterization of Imbutamine Analogs as Histamine H 3 and H 4 Receptor Ligands
Author(s) -
Geyer Roland,
Kaske Melanie,
Baumeister Paul,
Buschauer Armin
Publication year - 2014
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201300316
Subject(s) - selectivity , chemistry , histamine , stereochemistry , imidazole , agonist , histamine h3 receptor , receptor , histamine receptor , radioligand , antagonist , biochemistry , pharmacology , biology , catalysis
Imbutamine (4‐(1 H ‐imidazol‐4‐yl)butanamine) is a potent histamine H 3 (H 3 R) and H 4 receptor (H 4 R) agonist (EC 50 values: 3 and 66 nM, respectively). Aiming at improved selectivity for the H 4 R, 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 H 4 R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5‐Methylimbutamine (H 4 R: EC 50 = 59 nM, α = 0.8) was equipotent with imbutamine at the hH 4 R, but revealed about 16‐fold selectivity for the hH 4 R compared to the hH 3 R (EC 50 980 nM, α = 0.36), whereas imbutamine preferred the hH 3 R. 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 H 4 R.