title: Antagonism/Agonism modulation to build novel antihypertensives selectively triggering i1-imidazoline receptor activation.
abstract: 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.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Del Bello
authors.affiliation: Department NEUROFARBA, Preclinical and Clinical Pharmacology, University of Firenze , Viale Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bargelli
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Cifani
authors.affiliation: 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.
authors.forename: Paola
authors.initials: P
authors.lastname: Gratteri
authors.affiliation: Department of Chemistry Ugo Schiff, University of Firenze , Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Bazzicalupi
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Diamanti
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Mammoli
authors.affiliation: Department NEUROFARBA, Preclinical and Clinical Pharmacology, University of Firenze , Viale Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Matucci
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino , Via Madonna delle Carceri 9, 62032 Camerino, Italy.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Micioni Di Bonaventura
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino , Via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
keywords: I1-agonists; antihypertensive agents; bradicardic agents; carbomethyline; imidazoline compounds; stereoselectivity