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

Abstract As a continuation of our search for novel histamine H 3 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 H 3 receptor (hH 3 R). The highest affinities were observed for pentyl derivatives 6 – 8 ( K i  = 8.8–23.4 nM range) and among them piperidine derivative 6 with K i  = 8.8 nM. Structures 6 , 7 were also classified as antagonists in cAMP accumulation assay (with EC 50  = 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 hH 3 R (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.