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ACS Med Chem Lett. 2015 Apr 3;6(5):496-501. doi: 10.1021/acsmedchemlett.5b00115. eCollection 2015 May 14.

Antagonism/Agonism modulation to build novel antihypertensives selectively triggering i1-imidazoline receptor activation.

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School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
Department NEUROFARBA, Preclinical and Clinical Pharmacology, University of Firenze , Viale Pieraccini 6, 50139 Firenze, Italy.
School of Pharmacy, Pharmacology Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
Department NEUROFARBA, Pharmaceutical and Nutraceutical Section and Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze , via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
Department of Chemistry Ugo Schiff, University of Firenze , Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.


Pharmacological studies have suggested that I1-imidazoline receptors are involved in the regulation of cardiovascular function and that selective I1-agonists, devoid of the side effects associated with the common hypotensive α2-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 I1-agonist 4, we designed, prepared, and studied the novel analogues 5-9. A selective I1-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 I1 proteins.


I1-agonists; antihypertensive agents; bradicardic agents; carbomethyline; imidazoline compounds; stereoselectivity

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