Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine H3R ligands.
Eur J Med Chem
; 152: 223-234, 2018 May 25.
Article
in En
| MEDLINE
| ID: mdl-29723785
ABSTRACT
As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Kiâ¯=â¯16.0-120â¯nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H3R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10,in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperazines
/
Seizures
/
Receptors, Histamine H3
/
Histamine H3 Antagonists
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Eur J Med Chem
Year:
2018
Document type:
Article
Affiliation country:
Poland