Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, Université de Strasbourg, France.
J Pharmacol Exp Ther. 2013 Sep;346(3):370-80. doi: 10.1124/jpet.113.205328. Epub 2013 Jul 1.
Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy. LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride], a new pyrroline derivative, displaced the specific [(125)I]para-iodoclonidine binding to I1R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I1Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.
代谢综合征（MetS）的症状，如胰岛素抵抗、肥胖和高血压，与交感神经活性亢进有关。此外，脂联素途径在 MetS 中具有有趣的治疗潜力。我们的目的是研究用一种选择性非肾上腺素能 I1-咪唑啉受体（I1R）的药物靶向交感神经系统和脂肪组织（脂联素分泌），这可能是 MetS 药物治疗的新概念。LNP599[3-氯-2-甲基-苯基-（4-甲基-4,5-二氢-3H-吡咯-2-基）-胺盐酸盐]，一种新的吡咯烷衍生物，以纳摩尔亲和力置换特异性[（125）I]para-碘氯定与 I1R 的结合，并且对一大组受体、转运体和酶没有显著的亲和力。此外，它可以穿过血脑屏障，具有良好的肠道吸收性，允许口服和静脉给药。在 3T3-L1 脂肪细胞中存在 I1R；LNP599 对脂肪细胞中的脂联素分泌有特异性刺激作用。在麻醉的 Sprague-Dawley 大鼠中短期给予 LNP599（10mg/kg 静脉内）可显著降低交感神经活性，导致低血压和心动过缓。长期用 LNP599（20mg/kg 口服）治疗自发性高血压心力衰竭大鼠对血压、体重、胰岛素抵抗、葡萄糖耐量和血脂谱有有利影响，并增加血浆脂联素。抑制交感神经活性并刺激脂联素分泌的吡咯烷衍生物对所有 MetS 异常均有有益作用。使用一种具有这两种作用的单一药物可能是管理 MetS 的一种创新策略。
