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- Title
Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands<sup>†</sup>.
- Authors
Pockes, Steffen; Wifling, David; Buschauer, Armin; Elz, Sigurd
- Abstract
New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (2). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S‐methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies. Selectivity first! Structure‐activity relationship of 27 new ligands from the hetarylpropylguanidine‐type was investigated at the four histamine receptor subtypes with detailed pharmacological characterization. Methylisothiourea analogue 143 turned out to have high affinity at the hH4R with perceptible selectivity. Computational studies for 143 at both hH4R and hH3R were accomplished in order to gain more insight into the respective binding modes.
- Subjects
HISTAMINE receptors; STRUCTURE-activity relationships; FUNCTIONAL groups; GUINEA pigs; COMPUTATIONAL chemistry; GUANIDINE derivatives
- Publication
ChemistryOpen, 2019, Vol 8, Issue 3, p285
- ISSN
2191-1363
- Publication type
Article
- DOI
10.1002/open.201900011