Antagonism/Agonism Modulation to Build Novel Antihypertensives Selectively Triggering I1-Imidazoline Receptor Activation

被引：13

作者：

Del Bello, Fabio ^{[1
]}

Bargelli, Valentina ^{[2
]}

Cifani, Carlo ^{[3
]}

Gratteri, Paola ^{[4
,5
,6
]}

Bazzicalupi, Carla ^{[7
]}

Diamanti, Eleonora ^{[1
]}

Giannella, Mario ^{[1
]}

Mammoli, Valerio ^{[1
]}

Matucci, Rosanna ^{[2
]}

Di Bonaventura, Maria Vittoria Micioni ^{[3
]}

Piergentili, Alessandro ^{[1
]}

Quaglia, Wilma ^{[1
]}

Pigini, Maria ^{[1
]}

机构：

[1] Univ Camerino, Med Chem Unit, Sch Pharm, I-62032 Camerino, Italy

[2] Univ Florence, Dept NEUROFARBA, Preclin & Clin Pharmacol, I-50139 Florence, Italy

[3] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, Italy

[4] Univ Florence, Dept NEUROFARBA, Pharmaceut & Nutraceut Sect, I-50019 Florence, Italy

[5] Univ Florence, Lab Mol Modeling Cheminformat, I-50019 Florence, Italy

[6] Univ Florence, QSAR, I-50019 Florence, Italy

[7] Univ Florence, Dept Chem Ugo Schiff, I-50019 Florence, Italy

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 05期

关键词：

imidazoline compounds; I-1-agonists; antihypertensive agents; bradicardic agents; stereoselectivity; carbomethyline; ALPHA(2)-ADRENORECEPTORS PROFILE MODULATION; IMIDAZOLINE BINDING-SITES; KEY ROLE; MOXONIDINE; ANALOGS;

D O I：

10.1021/acsmedchemlett.5b00115

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pharmacological studies have suggested that I-1-imidazoline receptors are involved in the regulation of cardiovascular function and that selective I-1-agonists, devoid of the side effects associated with the common hypotensive alpha(2)-adrenoreceptor agonists, might be considered as a second generation of centrally acting antihypertensives. Therefore, in the present study, inspired by the antihypertensive behavior of our selective I-1-agonist 4, we designed, prepared, and studied the novel analogues 5-9. A selective I-1-profile, associated with significant hemodinamic effects, was displayed by 5, 8, and 9. Interestingly, the highest potency and longest lasting activity displayed by 8 (carbomethyline) suggested that van der Waals interactions, promoted by the ortho methyl decoration of its aromatic moiety, are particularly advantageous. In addition, in analogy to what was noted for (S)-(+)-4, the observation that only (S)-(+)-8 displayed significant hemodynamic effects unequivocally confirmed the stereospecific nature of the I-1 proteins.

引用

页码：496 / 501

页数：6

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