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.

Imidazoline Receptor System: The Past, the Present, and the Future

“…Their potential therapeutic applications are currently being studied. Such compounds could represent a basis for the development of drugs to be used in hypertension and perhaps for other indications, as discussed later in this review (Fellmann et al, 2013a;Gasparik et al, 2015). Once the concept of imidazoline receptors was accepted by a large number of scientists interested in the potential therapeutic effects and uses of drugs targeting these receptors, they were quickly subdivided into three subtypes: I 1 , I 2 and I 3 .…”

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

“…In general, methylation occurs on an activated substrate such as C‐halides (Cl, Br), C‐OTf, C‐OSO 2 C 6 F 5 , and halogenated acrylates . In many cases, methylation is carried out on late‐stage intermediates, and more interestingly, owing to the excellent functional group tolerance, TMB‐mediated methylation chemistry is often published in journals relevant to medicinal chemistry, in which functional groups, such as secondary amine, oxetane, acetal, aldehyde, ketone, imidazole, aniline, thiol ether, indole, ester, and amide are often designed into pharmaceutical molecules or their corresponding intermediates.…”

Methods of Pharmacological Correction of Ischemic Damages Insulated Leather Tissue by Agonists of Imidazoline Receptors

“…Описан еще один тип рецепторов, не относящихся ни к одному из упомянутых типов и локализующихся в симпатических нервных окончаниях. Их активация приводит к снижению выработки норадреналина [Gothert et al, 1999]. I1−рецепторы найдены также на мембранах тромбоцитов.…”

“…Гиперинсулинемия патогенетически связана с формированием артериальной гипертензии -инсулин повышает активность симпатической нервной системы, увеличивая тем самым сердечный выброс и периферическое сосудистое сопротивление. Агонисты центральных имидазолиновых рецепторов, напротив, оказывают центральное симпатолитическое действие [Gasparik et al, 2015]. В свою очередь, агонисты переферических имидазолиновых рецепторов, снижают инсулинорезистентность тканей, тем самым, снижая уровень инсулинемии [Lowry et al, 2014].…”

“…Агонисты центральных имидазолиновых рецепторов (IR1) (в рамках данного исследования -Моксонидин) реализуют своё дерматопротекторное действие за счёт своей вазодвигательной активности. Изменение тонуса сосудов кожи приводит к раскрытию дополнительных шунтов, обеспечивающих приток крови к участкам с редуцированным кровообращением [Gasparik et al, 2015].…”