title: Guanidine and 2-aminoimidazoline aromatic derivatives as alpha2-adrenoceptor antagonists. 2. Exploring alkyl linkers for new antidepressants.
abstract: The preparation of a number of (bis)guanidine and (bis)2-aminoimidazoline derivatives as potential alpha 2-adrenoceptor antagonists for the treatment of depression is presented. Human brain tissue was used to measure their affinity toward the alpha 2-adrenoceptors in vitro. Compounds 6b, 8b, 9b, 10b, 15b, 17b, 18b, 20b, and 21b displayed a good affinity (pKi > 7) and were evaluated in in vitro functional [(35)S]GTPgammaS binding assays in human prefrontal cortex to determine their agonistic or antagonistic activity. Among these compounds, 17b and 20b showed the expected behavior for an antagonist and were subject to in vivo microdialysis experiments in rats. Significantly, these experiments confirmed the antagonistic properties of 17b and 20b, and therefore both compounds can be considered as potential antidepressants.
authors.affiliation: Centre for Synthesis and Chemical Biology, School of Chemistry, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodriguez
authors.forename: Isabel
authors.initials: I
authors.lastname: Rozas
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Ortega
authors.forename: Amaia M
authors.initials: AM
authors.lastname: Erdozain
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048288:Imidazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C530308:4,4'-bis(2-imidazolidinylimino)-1,2-diphenylethane; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000928:Antidepressive Agents; D006146:Guanidines; D007093:Imidazoles; D048288:Imidazolines; C530307:N-(5,6,7,8-tetrahydronaphthalen-2-yl)guanidine; D013267:Stilbenes; D013764:Tetrahydronaphthalenes