Nicholson C D, Shahid M, Bruin J, Barron E, Spiers I, de Boer J, van Amsterdam R G, Zaagsma J, Kelly J J, Dent G
N.V. Organon Oss, The Netherlands.
J Pharmacol Exp Ther. 1995 Aug;274(2):678-87.
The pharmacological profile of a novel cyclic nucleotide phosphodiesterase (PDE) inhibitor, Org 20241, has been characterized. The compound selectively inhibits PDE IV (pIC50, 5.2-6.1) and PDE III (pIC50, 4.4-4.6) from animal and human tissues. Org 20241 relaxed preparations of bovine trachea (pD2, 5.9 and 5.4), guinea pig trachea (pD2, 6.2 and 4.9) and human bronchi (pD2, 5.3 and 4.7) for histamine and methacholine-induced contractions, respectively. Rolipram and Org 20241 inhibited leukotriene B4-induced thromboxaneB2 (IC50, 0.3 and 1.4 microM, respectively) and H2O2 (IC50, 2.1 and 0.4 microM, respectively) production in guinea pig eosinophils. In phenylephrine (0.3 microM) precontracted rabbit aorta preparations, the PDE III inhibitor Org 9935 (pD2, 6.3 and 6.1 in the presence and absence of endothelium, respectively) was the most effective relaxant, whereas Org 20241 (pD2, 5.3 and 5.4 in the presence and absence of endothelium, respectively) was more effective than rolipram (pD2, 4.6 and 4.1 in the presence and absence of endothelium, respectively). Org 20241 relaxed rabbit aorta preparations and airway preparations at similar concentrations. In electrically stimulated rabbit cardiac papillary muscles, Org 20241 had little effect on contractility at concentrations up to 30 microM. Lower concentrations (10 microM) potentiated the inotropic effect of Org 9935. Whereas the PDE III inhibitor milrinone (1-100 microM) enhanced the rate of repolarization of guinea pig papillary muscles and shortened the effective refractory period, Org 20241 and rolipram (1-100 microM) did not reduce the action potential duration. In the presence of Org 20241 or rolipram, isoproterenol did not produce a greater increase in the rate of repolarization or reduction in the effective refractory period than in the absence of these PDE inhibitors. Org 20241 is a dual PDE IV/III inhibitor with some PDE IV selectively. This compound relaxes airways smooth muscle and inhibits eosinophil activation. The data indicate that such PDE IV/III inhibitors may be effective for the long-term therapy of asthma.
一种新型环核苷酸磷酸二酯酶（PDE）抑制剂Org 20241的药理学特性已得到表征。该化合物可选择性抑制来自动物和人体组织的PDE IV（pIC50为5.2 - 6.1）和PDE III（pIC50为4.4 - 4.6）。Org 20241可分别使牛气管（pD2分别为5.9和5.4）、豚鼠气管（pD2分别为6.2和4.9）以及人支气管（pD2分别为5.3和4.7）的组胺和乙酰甲胆碱诱导的收缩舒张。咯利普兰和Org 20241分别抑制豚鼠嗜酸性粒细胞中白三烯B4诱导的血栓素B2（IC50分别为0.3和1.4微摩尔）以及过氧化氢（IC50分别为2.1和0.4微摩尔）的产生。在去氧肾上腺素（0.3微摩尔）预收缩的兔主动脉制剂中，PDE III抑制剂Org 9935（在内皮存在和不存在时pD2分别为6.3和6.1）是最有效的舒张剂，而Org 20241（在内皮存在和不存在时pD2分别为5.3和5.4）比咯利普兰（在内皮存在和不存在时pD2分别为4.6和4.1）更有效。Org 20241在相似浓度下可使兔主动脉制剂和气道制剂舒张。在电刺激的兔心脏乳头肌中，Org 20241在浓度高达30微摩尔时对收缩性几乎没有影响。较低浓度（10微摩尔）可增强Org 9935的正性肌力作用。虽然PDE III抑制剂米力农（1 - 100微摩尔）可提高豚鼠乳头肌的复极化速率并缩短有效不应期，但Org 20241和咯利普兰（1 - 100微摩尔）并未缩短动作电位持续时间。在存在Org 20241或咯利普兰的情况下，异丙肾上腺素相比不存在这些PDE抑制剂时，在复极化速率增加或有效不应期缩短方面并未产生更大的作用。Org 20241是一种具有一定PDE IV选择性的双PDE IV/III抑制剂。该化合物可舒张气道平滑肌并抑制嗜酸性粒细胞活化。数据表明，此类PDE IV/III抑制剂可能对哮喘的长期治疗有效。
