Burrell L M, Phillips P A, Stephenson J, Risvanis J, Hutchins A M, Johnston C I
Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
J Endocrinol. 1993 Aug;138(2):259-66. doi: 10.1677/joe.0.1380259.
A non-peptide, orally effective, vasopressin (AVP) V1 receptor antagonist 1-(1-[4-(3-acetylaminopropoxy) benzoyl]-4-piperidyl)-3,4-dihydro-2(1H)-quinolinone (OPC-21268) has recently been described. This paper reports the in-vitro and in-vivo characterization of OPC-21268 binding to vasopressin receptors in rat liver and kidney. OPC-21268 caused a concentration-dependent displacement of the selective V1 receptor antagonist radioligand, 125I-labelled [d(CH2)5,sarcosine7]AVP to V1 receptors in both rat liver and kidney medulla membranes. The concentration of OPC-21268 that displaced 50% of specific AVP binding (IC50) was 40 +/- 3 nmol/l for liver V1 and 15 +/- 2 nmol/l for kidney V1 receptors (mean +/- S.E.M.; n = 3). OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH2(9)]d(CH2)5,D-Ile2,Ile4] AVP binding to V2 receptors in renal medulla membranes (IC50 > 0.1 mmol/l). After oral administration to rats, OPC-21268 was an effective V1 antagonist in a time- and dose-dependent manner. Binding kinetic studies showed that OPC-21268 acted as a competitive antagonist at the liver V1 receptor in vitro and in vivo, in addition to its in-vitro competitive effects at the renal V1 receptor. OPC-21268 shows promise as an orally active V1 antagonist.
最近报道了一种非肽类、口服有效的血管加压素（AVP）V1受体拮抗剂1-(1-[4-(3-乙酰氨基丙氧基)苯甲酰基]-4-哌啶基)-3,4-二氢-2(1H)-喹啉酮（OPC-21268）。本文报道了OPC-21268与大鼠肝脏和肾脏中血管加压素受体结合的体外和体内特性。OPC-21268导致选择性V1受体拮抗剂放射性配体125I标记的[d(CH2)5,肌氨酸7]AVP在大鼠肝脏和肾髓质膜中与V1受体的浓度依赖性位移。使50%特异性AVP结合被取代（IC50）的OPC-21268浓度，对于肝脏V1受体为40±3 nmol/l，对于肾脏V1受体为15±2 nmol/l（平均值±标准误；n = 3）。OPC-21268对选择性V2拮抗剂放射性配体[3H]去甘氨酰胺（9）]d(CH2)5,D-异亮氨酸2,异亮氨酸4]AVP与肾髓质膜中V2受体的结合影响很小（IC50>0.1 mmol/l）。给大鼠口服后，OPC-21268以时间和剂量依赖性方式成为有效的V1拮抗剂。结合动力学研究表明，OPC-21268在体外和体内对肝脏V1受体均表现为竞争性拮抗剂，此外在体外对肾脏V1受体也有竞争性作用。OPC-21268有望成为一种口服活性V1拮抗剂。
