【摘 要】
：
Hypertension is a serious public health problem worldwide.MT-1207,chemically named 3-(4-(4-(1H-benzotriazole-1-yl)butyl)piperazine-1-yl)benzisothiazole hydrochloride,is a new chemical entity that has entered into clinical trial as antihypertensive agent i
【机 构】
：
Department of Pharmacology,Second Military Medical University/Naval Medical University,Shanghai 2004
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Hypertension is a serious public health problem worldwide.MT-1207,chemically named 3-(4-(4-(1H-benzotriazole-1-yl)butyl)piperazine-1-yl)benzisothiazole hydrochloride,is a new chemical entity that has entered into clinical trial as antihypertensive agent in China.In this paper we report the pharmacological profile of MT-1207 regarding its acute,subacute,and long-term effects on hypertensive animal models,and its actions on isolated organs in vitro as well as its molecular targets.Blood pressure(BP)was measured in conscious animals;amlodipine was taken as a positive control drug.We showed that both single dose of MT-1207(1.25-20 mg/kg,ig)in spontaneously hypertensive rats(SHR)and MT-1207(0.25-6 mg/kg,ig)in two-kidney one-clip(2K1C)dogs dose-dependently decreased BP.MT-1207 quickly decreased BP within 5 min after administration;the hypotensive effect lasted for 8 and 12 h,respectively,in SHR and 2K1C dogs without reflex increase in heart rate.Multiple doses of MT-1207(5 mg·kg-1·d-1 in SHR;2 mg·kg-1·d-1 in 2K1C dogs,for 7 days)significantly decreased BP,slightly reduced heart rate,and both of them recovered after withdrawal.Long-term administration of MT-1207(10 mg kg-1·d-1 for 4 months or more time)produced a stable BP reduction,improved baroreflex sensitivity,reduced renal and cardiovascular damage in SHR,and delayed stroke occurrence and death in stroke-prone SHR.In isolated rat aortic rings precontracted by adrenaline,KCI,noradrenaline or 5-hydroxytryptamine(5-HT),MT-1207(10-9-10-4 M)caused concentration-dependent relaxation.In a panel of enzyme activity or radioligand binding assays of 87 molecular targets,MT-1207 potently inhibited adrenergic α1A,α1B,α1D,and 5-HT2A receptors with Ki＜1 nM.The antagonism of MT-1207 against these receptors was confirmed in isolated rabbit arteries.We conclude that MT-1207 is a novel and promising single-molecule multitarget agent for hypertension treatment to reduce hypertensive organ damage and stroke mortality.
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