title: Guanidine-based α2-adrenoceptor ligands: Towards selective antagonist activity.
abstract: Depression has been linked to a selective increase in the high affinity conformation of the α2-adrenergic autoreceptors (α2-ARs) in the human brain as well as to an overexpression of α2-ARs in the hippocampus and cerebral cortex. Thus, the development of novel α2-AR antagonists represents an attractive source of new antidepressants. This paper describes the design, synthesis and pharmacological evaluation of 30 new guanidinium and 2-iminoimidazolidinium as potential α2-AR antagonists. In order to design this new series of α2-AR antagonists, a pharmacophore model was developed using the GALAHAD software. This study suggested that increased substitution in the space surrounding the cationic guanidine moiety might lead selectively to antagonist activity. Following the preparation of compounds incorporating this feature and competitive radioligand binding, [(35)S]GTPγS functional assays revealed that this structural modification affords exclusively α2-AR antagonists, in contrast with the analogous unsubstituted compounds in which a mixture of antagonist/agonist activities was previously observed.
authors.affiliation: School of Chemistry, TBSI, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: O'Donovan
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, and Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Muguruza
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, and 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, TBSI, 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: D004305:Dose-Response Relationship, Drug; D019791:Guanidine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2; D019791:Guanidine
keywords: Alpha 2-adrenoceptor; Antagonists; Human prefrontal cortex tissue; Pharmacophore; [(35)S]GTPγS