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ChemistryOpen Volume 8 ,Issue 3 ,2019-03-05
Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands†
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Steffen Pockes 1 David Wifling 1 Armin Buschauer 1 Sigurd Elz 1
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Received 2019-01-10,

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.


computational chemistry;organ pharmacology;receptor subtype selectivity;ligand design;histamine H receptor


© 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim


Structures of histamine and selected histamine receptor ligands (2–4).

Structures of the amines 5–7, which were used for the preparation of the final compounds 115–136 and 141–145 (cf. Scheme 1–3).

Synthesis of the precursors 17–27. Reagents and conditions: (a) CH3I (1.1 equiv), MeCN, 1 h, reflux; (b) NEt3 (1 equiv), Boc2O (2 equiv), overnight, room temperature (rt); (c) diamine (5 equiv), Boc2O (1 equiv), DCM, 2 h, 0 °C→rt; (d) diamine (3 equiv), 10 (1 equiv), DCM, overnight, rt.

Synthesis of the HR ligands 115–136. Reagents and conditions: (a) amine/diamine (1 equiv), 28 (1 equiv/2 equiv), DCM, 2 h/overnight, 0 °C→rt; (b) K2CO3 (2.1 equiv/4.1 equiv), MeOH/H2O (7/3, v/v), 3–5 h, rt; (c) CH3I (1.1 equiv/2.1 equiv), MeCN, 1 h, reflux; (d) NEt3 (1 equiv/2 equiv), Boc2O (1 equiv/2 equiv), overnight, rt; (e) 5, 6 or 7 (1 equiv/2 equiv), HgCl2 (1 equiv/4 equiv), NEt3 (3 equiv/6 equiv), DCM, overnight, rt; (f) 20 % TFA, DCM, overnight, reflux.

Synthesis of the SK&F 91486 analogues 141–145. Reagents and conditions: (a) 5 (1 equiv), 28 or 138 (1 equiv), DCM, overnight, 0 °C→rt; (b) K2CO3 (2.1 equiv), MeOH/H2O (7/3, v/v), 3–5 h, rt; (c) 20 % TFA, DCM, overnight, reflux; (d) i) 66 % HI, EtOH, rt; ii) CH3I (1.1 equiv), MeOH 1 h, reflux; (e) NaOH (1 M solution), 1 h, reflux.

Selectivity profile of 143 with radioligand displacement curves from radioligand binding assays. Experiments were performed with compound 143 and [3H]mepyramine (hH1R, Kd 4.5 nM, c=5 nM), [3H]tiotidine (hH2R, Kd 19.7 nM, c=10 nM), [3H]Nα‐methylhistamine (hH3R, Kd 8.6 nM, c=3 nM) or [3H]histamine (hH4R, Kd 16.0 nM, c=15 nM) at membranes of Sf9 cells expressing the respective hHR. Data represent mean values ± SEM from at least two independent experiments, each performed in triplicate.

Concentration‐response curves of 1, 2 and 3 (black), as well as 116, 120, 124, 129, 133, 143 and 144 (colored) at the gpH2R (atrium). Histamine (1) was used as a reference (pEC50=6.16, Emax=1.00). Displayed curves are calculated by endpoint determination (N=1).

Lowest free energy (MM‐GBSA) docking poses of 143 at both the hH4R (A, B) and hH3R (C, D) showing key ligand‐receptor interactions in the form of ligand interaction diagrams (A, C) or three‐dimensional illustrations (B, D). Hydrogen bonds and salt bridges are colored in magenta (A, C) or yellow (B, D), and cation‐π interactions in red (A, C).

Table 1

Table 2

Table 3


Steffen Pockes.Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053, Regensburg, Germany.steffen.pockes@ur.de


Steffen Pockes,David Wifling,Armin Buschauer,Sigurd Elz. Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands†. ChemistryOpen ,Vol.8, Issue 3(2019)



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