（噻吩亚基）-3,4-亚甲二氧基苯甲酰肼的药理学特性：一种具有降压作用的新型毒蕈碱激动剂。

Pharmacological characterization of (3-thienylidene)-3,4-methylenedioxybenzoylhydrazide: a novel muscarinic agonist with antihypertensive profile.

机构信息

Programa de Desenvolvimento de Fármacos, Departamento de Farmacologia Basica e Clinica, ICB, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

出版信息

Am J Hypertens. 2010 Feb;23(2):135-41. doi: 10.1038/ajh.2009.238. Epub 2009 Dec 3.

DOI:10.1038/ajh.2009.238

PMID:19959998

Abstract

BACKGROUND

Several new bioactive compounds of the N-acylhydrazone class were developed from the safrole, a Brazilian natural product obtained from sassafras oil (Ocotea pretiosa). This work investigated the effects on cardiovascular system of LASSBio-897, a new analogue of the lead compound 3,4-methylenedioxybenzoyl-2-thienylhydrazone named LASSBio-294.

METHODS

Thoracic aorta from Wistar-Kyoto (WKY) rats was prepared for isometric tension recording and for cGMP content determination. Blood pressure (BP) was measured in WKY rats and spontaneously hypertensive rats (SHR) after treatment with 1 mg/kg intravenously of LASSBio-897 and during 14 days' treatment of SHR with 1 mg/kg/day perorally.

RESULTS

LASSBio-897 (0.05-1 micromol/l) exhibited a potent vasodilatory activity in phenylephrine (Phe)-contracted aortic rings from WKY rats. This effect was abolished in endothelium-denuded aortic rings and after treatment with the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) or the guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Also, LASSBio 897 (1 micromol/l) increased about 15 times the intracellular content of cGMP. LASSBio-897-induced vasodilation was totally inhibited by the muscarinic antagonist atropine and by the M(3) subtype selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), indicating the involvement of M(3) receptors. Intravenous administration of LASSBio-897 (1 mg/kg) produced significant hypotensive response in both WKY and SHR. The hypotensive effect of LASSBio-897 was also observed during the 14 days of oral administration.

CONCLUSIONS

The novel N-acylhydrazone derivative LASSBio-897 exhibited a potent vasodilatory activity in aortic rings mediated by the NO/cGMP pathway via activation of endothelial M(3) receptors and was orally effective in reducing BP on SHR.

摘要

背景

几种新的 N-酰腙类生物活性化合物是从巴西天然产物黄樟油（Ocotea pretiosa）中提取的 safrole 开发而来的。这项工作研究了新型类似物 LASSBio-897 对心血管系统的影响，LASSBio-897 是 lead compound 3,4-亚甲二氧基苯甲酰基-2-噻吩基腙的一种类似物，名为 LASSBio-294。

方法

从 Wistar-Kyoto（WKY）大鼠的胸主动脉中制备等长张力记录和 cGMP 含量测定。静脉内给予 1mg/kg LASSBio-897 后，在 WKY 大鼠和自发性高血压大鼠（SHR）中测量血压（BP），并在 SHR 每天口服 1mg/kg 治疗 14 天期间进行测量。

结果

LASSBio-897（0.05-1μmol/L）在 Phe 收缩的 WKY 大鼠主动脉环中表现出强大的血管扩张活性。这种作用在去内皮的主动脉环中被消除，并且在用一氧化氮（NO）合酶抑制剂 N(G)-硝基-L-精氨酸甲酯（L-NAME）或鸟苷酸环化酶抑制剂 1H-[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮（ODQ）处理后被消除。此外，LASSBio 897（1μmol/L）使细胞内 cGMP 含量增加约 15 倍。LASSBio-897 诱导的血管舒张完全被毒蕈碱拮抗剂阿托品和 M(3)亚型选择性拮抗剂 4-二苯乙酰氧基-N-甲基哌啶甲碘化物（4-DAMP）抑制，表明 M(3)受体的参与。静脉内给予 LASSBio-897（1mg/kg）在 WKY 和 SHR 中均产生显著的降压反应。在口服给药的 14 天内也观察到 LASSBio-897 的降压作用。