Synthesis and biological activity of novel tert-amylphenoxyalkyl (homo)piperidine derivatives as histamine H3R ligands.
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=8.8-23.4nM range) and among them piperidine derivative 6 with Ki=8.8nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50=157 and 164nM, 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 30mg/kg at 0.5h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300mg/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.
['Kuder|Kamil J|KJ|', 'Łażewska|Dorota|D|', 'Kaleta|Maria|M|', 'Latacz|Gniewomir|G|', 'Kottke|Tim|T|', 'Olejarz|Agnieszka|A|', 'Karcz|Tadeusz|T|', 'Fruziński|Andrzej|A|', 'Szczepańska|Katarzyna|K|', 'Karolak-Wojciechowska|Janina|J|', 'Stark|Holger|H|', 'Kieć-Kononowicz|Katarzyna|K|']
D000818:Animals D000927:Anticonvulsants D001665:Binding Sites D002460:Cell Line D049109:Cell Proliferation D004597:Electroshock D057809:HEK293 Cells D054828:Histamine H3 Antagonists D006801:Humans D008297:Male D051379:Mice D062105:Molecular Docking Simulation D009474:Neurons D010880:Piperidines D011485:Protein Binding D017434:Protein Structure, Tertiary D051381:Rats D017207:Rats, Sprague-Dawley D018100:Receptors, Histamine H3 D012995:Solubility
Piperidine derivatives Anticonvulsants Drug-like properties Histamine H(3) receptor Histamine H(3) receptor ligands Molecular docking Non-imidazole histamine H(3)R ligands