Synthesis and biological activity of novel tert-amylphenoxyalkyl (homo)piperidine derivatives as histamine H3R ligands

Publication date: Available online 21 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kamil Kuder, Dorota Łażewska, Maria Kaleta, Gniewomir Latacz, Tim Kottke, Agnieszka Olejarz, Tadeusz Karcz, Andrzej Fruziński, Katarzyna Szczepańska, Janina Karolak-Wojciechowska, Holger Stark, Katarzyna Kieć-Kononowicz
As a continuation of our search for novel histamine H3 receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2-21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for pentyl derivatives 6-8 (Ki= 8.8 – 23.4 nM range) and among them piperidine derivative 6 with Ki=8.8 nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50 = 157 and 164 nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2-4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30 mg/kg at 0.5 h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300 mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate "drug-likeness" of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed.

Graphical abstract

http://ift.tt/2nAs4hj