Synthesis and biological evaluation of heteroalicyclic cyanoguanidines at histamine receptors

Recent studies on histamine receptor (HR) subtypes identified imidazolyl butyl cyanoguanidines, like UR-PI376, as highly potent agonists at the human histamine H₄ receptor (hH₄R). 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 (C₃–C₅) 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 hH₁R and hH₃R, while nearly all compounds were inactive at the hH₂R and hH₄R. In the case of piperidine-containing compounds, moderate affinities at the hH₃R over the single-digit micromolar range were detected.