title: α2-adrenoceptor antagonists: synthesis, pharmacological evaluation, and molecular modeling investigation of pyridinoguanidine, pyridino-2-aminoimidazoline and their derivatives.
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.
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Kelly
authors.forename: Michela
authors.initials: M
authors.lastname: McMullan
authors.forename: Carolina
authors.initials: C
authors.lastname: Muguruza
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Ortega
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
authors.forename: Isabel
authors.initials: I
authors.lastname: Rozas
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D006146:Guanidines; D048288:Imidazolines