848861-40-5Relevant academic research and scientific papers
Search for histamine H3 receptor ligands with combined inhibitory potency at histamine N-methyltransferase: ω- piperidinoalkanamine derivatives
Grassmann, Sven,Apelt, Joachim,Ligneau, Xavier,Pertz, Heinz H.,Arrang, Jean-Michel,Ganellin, C. Robin,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
, p. 533 - 545 (2007/10/03)
In an effort to design new hybrid compounds with dual properties, i.e. binding affinity at histamine H3 receptors and inhibitory potency at the catabolic enzyme histamine Nτ-methyltransferase (HMT), a novel series of 1-substituted piperidine derivatives was synthesized. This alicyclic heterocycle is structurally linked via aminoalkyl spacers of variable lengths to additional aromatic carbo- or heterocycles. These new hybrid drugs were pharmacologically evaluated regarding their binding affinities at recombinant human H3 receptors, stably expressed in CHO cells, and in a functional assay for their inhibitory potencies at rat kidney HMT. All compounds investigated proved to be H3 receptor ligands with binding affinities in the micro- to nanomolar concentration range despite significant differences in the type of the aromatic moiety introduced. The most potent compound in this series was the quinoline derivative 20 (Ki = 5.6 nM). Likewise, all new ligands studied showed impressive HMT inhibitory activities. Here, compounds 5, 10, 14, and 18-20 exhibited submicromolar potencies (IC50 = 0.061 -0.56 μM). The aminomethylated quinoline 19 showed almost the same, well balanced nanomolar activities on both targets. In this study, new hybrid compounds with a dual mode biological action were developed. These pharmacological agents are valuable leads for further development and candidates for treatment of histamine-dependent disorders.
