Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands^†

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 (H 1 R, H 2 R, H 3 R, H 4 R) 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 ( gp H 1 R) and right atrium ( gp H 2 R). 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 ) H 3 R, S‐methylisothiourea analogue 143 obtained high affinity at the h H 4 R (pK i =8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.

Synthesis and biological evaluation of heteroalicyclic cyanoguanidines at histamine receptors

“…Coming from the lead structure SK&F 91486 (Figure ) , several potent ligands for HR subtypes, especially the hH 2 R, hH 3 R, and hH 4 R, were synthesized containing an aromatic heterocycle (imidazole and aminothiazole) and a substituted guanidine partial structure linked with a methylene spacer. Aiming at selectivity for the respective receptors, a series of alkylated, acylated, carbamoylated guanidines as well as cyanoguanidines, were identified as potent HR agents. Previous studies have already investigated the influence of substituted cyanoguanidines on the activity of HR subtypes .…”

Histamine H 2 Receptor Radioligands: Triumphs and Challenges

“…In contrast, H 2 receptor agonists have not yet found their way into the world's drug portfolio. Although a large number of highly potent and subtypeselective agonists has already been published, these ligands are predominantly applied in basic research studies within academia [11][12][13][14][15][16][17][18]. However, the aforementioned properties turn them into valuable pharmacological tools that could be of great importance to elucidate the largely unknown role of the H 2 R in the central nervous system (CNS) [3,15].…”