title: New 2-Aminothiazoline derivatives lower blood pressure of spontaneously hypertensive rats (SHR) via I1-imidazoline and alpha-2 adrenergic receptors activation.
abstract: 2-Aminothiazolines share an isosteric relationship with imidazolines and oxazolines with antihypertensive activity mainly mediated by the imidazoline I1-receptor. In the present work, we have prepared five aminothiazolines, following a previously described synthetic pathway. Aminothiazolines derived from dicyclopropylmethylamine (ATZ1) and cyclohexylamine (3) are unprecedented in the literature. Competitive radioligand assay was carried out with all synthetic compounds, and the I1receptor affinity in comparison to rilmenidine in PC12 cells was determined. Surprisingly, the rilmenidine isoster (ATZ1) showed no I1-receptor interaction. Diethyl (ATZ4) and 2-ethyl-hexylamine (ATZ5) derivatives bind to the receptor with 11.98 and 10.94nmol/l, respectively. These compounds were selected for in vivo experiments. Both compounds reduced the blood pressure of spontaneously hypertensive rats (SHR). The hypotensive effect of these compounds was abrogated in the presence of α2adrenergic (yohimbine) and I1(efaroxan) receptor antagonists suggesting that both aminothiazolines bind to the adrenergic and imidazoline receptors. Lipinski's descriptors of the synthesized aminothiazolines were calculated and are similar to the known imidazoline I1receptor ligands. 3D-Similarity between ATZ5 and agmatine, the natural imidazoline receptor ligand, was also observed.
authors.affiliation: Institute of Chemistry, University of Campinas, PO Box 6194, ZC 13083-970 Campinas, SP, Brazil.
authors.forename: Renan B
authors.initials: RB
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: Mariana G
authors.initials: MG
authors.lastname: de Oliveira
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Campinas, PO Box 6029, ZC 13083-859 Campinas, SP, Brazil. Electronic address: wanda.almeida@fcf.unicamp.br.
authors.forename: Wanda P
authors.initials: WP
authors.lastname: Almeida
authors.affiliation: Department of Pharmacology and Toxicology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Badr M
authors.initials: BM
authors.lastname: Ibrahim
authors.affiliation: Department of Pharmacology and Toxicology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel-Rahman
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D016716:PC12 Cells; D051381:Rats; D011918:Rats, Inbred SHR; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D018341:Receptors, Adrenergic, alpha-2; D013844:Thiazoles; C410887:imidazoline I1 receptors; C031363:2-aminothiazoline; C062597:efaroxan
keywords: Aminothiazoline; Binding assay; Hypertension; Imidazoline receptor; PC12 cells