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Synthesis and biological evaluation of heteroalicyclic cyanoguanidines at histamine receptors
Author(s) -
Soliman Beatrice,
Wang Ning,
Zagotto Giuseppe,
Pockes Steffen
Publication year - 2019
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.201900107
Subject(s) - piperidine , morpholine , chemistry , stereochemistry , imidazole , moiety , histamine receptor , histamine , radioligand , receptor , affinities , piperazine , ring (chemistry) , pharmacology , medicinal chemistry , biochemistry , organic chemistry , biology , antagonist
Recent studies on histamine receptor (HR) subtypes identified imidazolyl butyl cyanoguanidines, like UR‐PI376, as highly potent agonists at the human histamine H 4 receptor (hH 4 R). While imidazole‐containing compounds display drawbacks in pharmacokinetics, we studied the possibility of replacing the heteroaromatic cycle by nonaromatic six‐membered heterocycles (piperidine, morpholine, thiomorpholine, and N ‐methylpiperazine) as potential bioisosteres. Beyond that, this approach should give more information about the indispensability of the aromatic ring as a basic head group. Besides these changes, a variation of the spacer length (C 3 –C 5 ) connecting the heterocycle and the cyanoguanidine moiety has been made to possibly trigger the selectivity towards the respective HRs. Investigations in radioligand‐binding assays exhibited only very weak activity at the hH 1 R and hH 3 R, while nearly all compounds were inactive at the hH 2 R and hH 4 R. In the case of piperidine‐containing compounds, moderate affinities at the hH 3 R over the single‐digit micromolar range were detected.