title: Substituted conformationally restricted guanidine derivatives: Probing the α2-adrenoceptors' binding pocket.
abstract: In this paper we report the design, synthesis and pharmacological evaluation of new N-substituted 2-amino-1,4-dihydroquinazolines, 2-amino-1,4-dihydropyridopyrimidines and 2-amino-4,5-dihydro-1,3-benzodiazepines as α2-adrenoceptors ligands. Computational studies show that the proposed substitutions and guanidine-containing ring size will probe an extensive area of the active site. Preparation of these molecules involved novel routes than those previously utilised in our laboratory for the preparation of the acyclic aryl-guanidine counterparts. Compounds 8b and 18c showed the highest affinity and antagonistic activity, within their series, towards the α2-adrenoceptor in human brain tissue in vitro experiments. Structure-activity relationships have been established for the design and biological evaluation of novel α2-adrenoceptor ligands.
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Michela
authors.initials: M
authors.lastname: McMullan
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
authors.forename: Aintzane
authors.initials: A
authors.lastname: García-Bea
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Miranda-Azpiazu
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland. Electronic address: rozasi@tcd.ie.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rozas
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000737:chemistry*; D001665:Binding Sites; D001921:Brain / Q000166:cytology / Q000378:metabolism; D015195:Drug Design; D019791:Guanidine / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2; D019791:Guanidine
keywords: 2-Amino-1,4-dihydropyridopyrimidines; 2-Amino-1,4-dihydroquinazolines; 2-Amino-4,5-dihydro-1,3-benzodiazepines; Conformationally restricted guanidines; Human brain tissue in vitro experiments; α(2)-adrenoceptors’ antagonists; α(2)-adrenoceptors’ ligands