Gasparik Vincent, Greney Hugues, Schann Stephan, Feldman Josiane, Fellmann Lyne, Ehrhardt Jean-Daniel, Bousquet Pascal
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, EA 7296, Fédération de Médecine Translationnelle, Université de Strasbourg , 11 rue Humann, 67000 Strasbourg, France.
J Med Chem. 2015 Jan 22;58(2):878-87. doi: 10.1021/jm501456p. Epub 2014 Dec 31.
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.
合成了新型2-芳基亚氨基吡咯烷（1-18），并测试了它们对I1咪唑啉受体与α2-肾上腺素能受体的结合特性，以及全身给药和脑内给药后的血压效应。本研究的目的是：（i）分析I1咪唑啉受体上的构效关系和亲和力关系；（ii）提出一些先导化合物，用于开发在高血压和/或代谢综合征（即一组心血管（高血压）和代谢紊乱）中有潜在应用的新型交感神经抑制药物。我们的研究突出了关于2-芳基亚氨基吡咯烷对I1受体的亲和力和降压活性的构效关系的决定性论据。结合试验表明，一些化合物对I1咪唑啉受体的亲和力和选择性高于α2-肾上腺素能受体。化合物13（实验室参考LNP599；对I1咪唑啉受体的Ki = 3.2 nM）是开发新型中枢作用药物的原型，该药物专门靶向I1咪唑啉受体，用于治疗高血压和/或代谢综合征。
