Guanidine and 2-Aminoimidazoline Aromatic Derivatives as α2-Adrenoceptor Antagonists. 2. Exploring Alkyl Linkers for New Antidepressants

The preparation of a number of (bis)guanidine and (bis)2-aminoimidazoline derivatives as potential α2-adrenoceptor antagonists for the treatment of depression is presented. Human brain tissue was used to measure their affinity toward the α2-adrenoceptors in vitro. Compounds 6b, 8b, 9b, 10b, 15b, 17b...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 51; no. 11; pp. 3304 - 3312
Main Authors Rodriguez, Fernando, Rozas, Isabel, Ortega, Jorge E, Erdozain, Amaia M, Meana, J. Javier, Callado, Luis F
Format Journal Article
LanguageEnglish
Published Washington, DC American Chemical Society 12.06.2008
Subjects
Biological and medical sciences
Catecholaminergic system
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
α2-Adrenergic receptor
Imidazole derivatives
Spacer arm
Rat
Psychotropic
Rodentia
Imidazoline derivatives
Guanidines
In vitro
In vivo
Vertebrata
Mammalia
Microdialysis
Structure activity relation
Animal
Antidepressant agent
Aromatic compound
Antagonist
Chemical synthesis
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ISSN0022-2623
1520-4804
DOI10.1021/jm800026x

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Summary:The preparation of a number of (bis)guanidine and (bis)2-aminoimidazoline derivatives as potential α2-adrenoceptor antagonists for the treatment of depression is presented. Human brain tissue was used to measure their affinity toward the α2-adrenoceptors in vitro. Compounds 6b, 8b, 9b, 10b, 15b, 17b, 18b, 20b, and 21b displayed a good affinity (pK i > 7) and were evaluated in in vitro functional [35S]GTPγS 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.
Bibliography:Preparation and IR, 1H NMR, 13C NMR, and MS data for the compounds already described in the literature (5b–7b, 9b, 11b–13b, 14a, 14b–16b, 22a, 22b, and 23b) and all new Boc-protected derivatives prepared (4a–13a, 15a–21a, and 23a); a table containing the combustion analysis data for the new final compounds (4b, 8b, 10b, and 17b–21b); and preparation of membranes, analysis of binding data, and drugs used in the pharmacology experiments. This material is available free of charge via the Internet at http://pubs.acs.org.
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ark:/67375/TPS-K3BSB3NX-2
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800026x