Synthesis and biological activity of novel tert-amylphenoxyalkyl (homo)piperidine derivatives as histamine H3R ligands. Issue 10 (15th May 2017)

• Record Type: Journal Article
• Authors: Kuder, Kamil J.; Łażewska, Dorota; Kaleta, Maria; Latacz, Gniewomir; Kottke, Tim; Olejarz, Agnieszka; Karcz, Tadeusz; Fruziński, Andrzej; Szczepańska, Katarzyna; Karolak-Wojciechowska, Janina; Stark, Holger; Kieć-Kononowicz, Katarzyna
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 10(2017)
• Page Start: 2701
• Page End: 2712
• Publication Date: 2017-05-15
• Subjects: Histamine H3 receptor -- Histamine H3 receptor ligands -- Non-imidazole histamine H3R ligands -- Piperidine derivatives -- Anticonvulsants -- Molecular docking -- Drug-like properties; NLVYWCRLGFDESU-UHFFFAOYSA-N -- CUKJWVHEMLBESD-UHFFFAOYSA-N -- POQQPNLUXGVXQL-UHFFFAOYSA-N -- WUWSDBLNZJIRHW-UHFFFAOYSA-N -- ZTNOXDYSIFPOBI-UHFFFAOYSA-N -- NABGTSWKHZDURR-UHFFFAOYSA-N -- QHLCQRLEFPCFJI-UHFFFAOYSA-N -- NTMAHDOXEBKVCH-UHFFFAOYSA-N -- QGGWOUVIJJJJEP-UHFFFAOYSA-N -- ZNIBZXYWEHLBPD-UHFFFAOYSA-N -- UESFTYGAZXOTRU-UHFFFAOYSA-N -- AYKJGACMCQMMAW-UHFFFAOYSA-N -- NVODSBDSTGAOMT-UHFFFAOYSA-N -- FWWPKYOBCUXAGM-UHFFFAOYSA-N -- OGOMRHOWEGLGBX-UHFFFAOYSA-N -- VYNGDPLRECMOSF-UHFFFAOYSA-N -- MKYGVSXNJQDMLW-UHFFFAOYSA-N -- GBEKSZVQFLMGCF-UHFFFAOYSA-N -- HZDUQTXNWTWVGF-UHFFFAOYSA-N -- OCDZXKYOYHCDPQ-UHFFFAOYSA-N -- LAKVEWGOEMZVEF-UHFFFAOYSA-N; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.03.031
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Series of twenty tert -amyl phenoxyalkylamine derivatives (2 –21 ) was synthesized. Compounds evaluated at hH3 R in binding affinity tests demonstrated K i values at 8.8–325 nM range. Anticonvulsant activity at MES, scMet and neurotoxicity tests were evaluated for selected compounds. X-ray structure analysis of compound18 was performed. Molecular modeling was performed and "drug-like" properties were estimated. Abstract: 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 (hH3 R). The highest affinities were observed for pentyl derivatives6 –8 ( K i = 8.8–23.4 nM range) and among them piperidine derivative6 with K i = 8.8 nM. Structures6, 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 and20 ) 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 compound4 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 hH3 R (taking into the consideration X-ray analysis of compound18 ). In order to estimate "drug-likeness" of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed.