Chlorophenoxy aminoalkyl derivatives as histamine H(3)R ligands and antiseizure agents.

Abstract A series of twenty new chlorophenoxyalkylamine derivatives ( 9 – 28 ) was synthesized and evaluated on their binding properties at the human histamine H 3 receptor (hH 3 R). The spacer alkyl chain contained five to seven carbon atoms. The highest affinities have shown the 4-chloro substituted derivatives 10 and 25 ( K i  = 133 and 128 nM, respectively) classified as antagonists in cAMP accumulation assay (EC 50  = 72 and 75 nM, respectively). Synthesized compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Two compounds (4-chloro substituted derivatives: 20 and 26 ) were the most promising and showed in the MES seizure model in rats (after ip administration) ED 50 values of 14 mg/kg and 13.18 mg/kg, respectively. Protective indexes (PI = TD 50 /ED 50 ) were 3.2 for 20 and 3.8 for 26 . Moreover, molecular modeling and docking studies were undertaken to explain affinity at hH 3 R of target compounds, and the experimentally and in silico estimation of properties like lipophilicity and metabolism was performed. Antiproliferative effects have been also investigated in vitro for selected compounds ( 10 and 25 ). These compounds neither possessed significant antiproliferative and antitumor activity, nor modulated CYP3A4 activity up to concentration of 10 μM.