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α2-adrenoceptor antagonists: synthesis, pharmacological evaluation, and molecular modeling investigation of pyridinoguanidine, pyridino-2-aminoimidazoline and their derivatives.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Jan 22; Vol. 58 (2), pp. 963-77. Date of Electronic Publication: 2015 Jan 02. - Publication Year :
- 2015
-
Abstract
- We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the α2-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacological evaluation of a new series of pyridine derivatives [para substituted 2- and 3-guanidino and 2- and 3-(2-aminoimidazolino)pyridines, disubstituted 2-guanidinopyridines and N-substituted-2-amino-1,4-dihydroquinazolines] that were found to be antagonists/inverse agonists of the α2-adrenoceptor. Furthermore, the compounds exert their effects at the α2-adrenoceptor both in vitro in human prefrontal cortex tissue and in vivo in rat brain as shown by microdialysis experiments. We also provide a docking study at the α2A- and α2C-adrenoceptor subtypes demonstrating the structural features required for high affinity binding to the receptor.
- Subjects :
- Adrenergic alpha-2 Receptor Antagonists chemistry
Adrenergic alpha-2 Receptor Antagonists pharmacology
Animals
Guanidines chemical synthesis
Guanidines pharmacology
Humans
Imidazolines chemical synthesis
Imidazolines pharmacology
Male
Models, Molecular
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Adrenergic alpha-2 Receptor Antagonists chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25490760
- Full Text :
- https://doi.org/10.1021/jm501635e