title: Synthesis and biological evaluation of 2-aryliminopyrrolidines as selective ligands for I1 imidazoline receptors: discovery of new sympatho-inhibitory hypotensive agents with potential beneficial effects in metabolic syndrome.
abstract: New 2-aryliminopyrrolidines (1-18) were synthesized and tested for their binding properties on I1 imidazoline receptors vs α2-adrenergic receptors and their blood pressure effects after both systemic and intracerebral administrations. The purposes of this study were: (i) to analyze structure-activity and affinity relationships on I1 imdazoline receptors and (ii) to propose some leader compounds for the development of new sympatho-inhibitory drugs with potential applications in hypertension and/or metabolic syndrome, i.e., a cluster of cardiovascular (hypertension) and metabolic disorders. Our study highlights decisive arguments of SAR concerning both the affinity for I1Rs and the hypotensive activity of 2-aryliminopyrrolidines. Binding assays showed high affinity and selectivity of some compounds for I1 imidazoline receptors over α2-adreergic receptors. Compound 13 (laboratory reference LNP599; Ki = 3.2 nM on I1imidazoline receptors) is the prototype for the development of new centrally acting agents targeting specifically I1imidazoline receptors to be used in the management of hypertension and/or metabolic syndrome.
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, EA 7296, Fédération de Médecine Translationnelle, Université de Strasbourg , 11 rue Humann, 67000 Strasbourg, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gasparik
authors.forename: Hugues
authors.initials: H
authors.lastname: Greney
authors.forename: Stephan
authors.initials: S
authors.lastname: Schann
authors.forename: Josiane
authors.initials: J
authors.lastname: Feldman
authors.forename: Lyne
authors.initials: L
authors.lastname: Fellmann
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Ehrhardt
authors.forename: Pascal
authors.initials: P
authors.lastname: Bousquet
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier; D055808:Drug Discovery; D006339:Heart Rate / Q000187:drug effects; D054755:Imidazoline Receptors / Q000378:metabolism*; D008024:Ligands; D024821:Metabolic Syndrome / Q000188:drug therapy*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013565:Sympatholytics / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D054755:Imidazoline Receptors; D008024:Ligands; D011759:Pyrrolidines; D013565:Sympatholytics; C410887:imidazoline I1 receptors