Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
J Pharmacol Exp Ther. 2010 Oct;335(1):249-55. doi: 10.1124/jpet.110.169748. Epub 2010 Jul 21.
Selexipag [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide] is an orally available prostacyclin (PGI(2)) receptor (IP receptor) agonist that is chemically distinct from PGI(2) and is in clinical development for the treatment of pulmonary arterial hypertension. Selexipag is highly selective for the human IP receptor in vitro, whereas analogs of PGI(2) can activate prostanoid receptors other than the IP receptor. The goal of this study was to determine the impact of selectivity for the IP receptor on gastric function by measuring 1) contraction of rat gastric fundus ex vivo and 2) the rates of gastric emptying and intestinal transport in response to selexipag in comparison with other PGI(2) analogs. The rat gastric fundus expresses mRNA encoding multiple prostanoid receptors to different levels: prostaglandin E receptor 1 (EP(1)) > prostaglandin E receptor 3 (EP(3)), IP receptor > prostaglandin D(2) receptor 1, thromboxane receptor. Selexipag and metabolite {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) did not contract gastric fundus at concentrations up to 10(-3) M. In contrast, the PGI(2) analogs iloprost and beraprost evoked concentration-dependent contraction of gastric fundus. Contraction to treprostinil was observed at high concentration (10(-4) M). Contraction to all PGI(2) analogs was mediated via activation of EP(3) receptors, although EP(1) receptors also contributed to the contraction of gastric fundus to iloprost and beraprost. Antagonism of IP receptors did not affect responses. Oral selexipag did not significantly alter gastric function in vivo, as measured by rates of stomach emptying and intestinal transport, whereas beraprost slowed gastrointestinal transport. The high functional selectivity of selexipag and ACT-333679 for the IP receptor precludes a stimulatory action on gastric smooth muscle and may help minimize gastric side effects such as nausea and vomiting.
塞来昔帕[2-{4-[(5,6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}-N-(甲基磺酰基)乙酰胺]是一种口服有效的前列环素（PGI(2)）受体（IP 受体）激动剂，与 PGI(2)在化学上不同，目前正在开发用于治疗肺动脉高压。塞来昔帕在体外对人 IP 受体具有高度选择性，而 PGI(2)的类似物可以激活除 IP 受体以外的前列腺素受体。本研究的目的是通过测量 1）大鼠胃底的离体收缩和 2）与其他 PGI(2)类似物相比，塞来昔帕对胃排空和肠道转运的作用，来确定对 IP 受体的选择性对胃功能的影响。大鼠胃底表达多种前列腺素受体的 mRNA，其表达水平不同：前列腺素 E 受体 1（EP(1)）>前列腺素 E 受体 3（EP(3)），IP 受体>前列腺素 D(2)受体 1，血栓素受体。塞来昔帕和代谢物{4-[(5,6-二苯基吡嗪-2-基)(异丙基)氨基]丁氧基}乙酸（ACT-333679）在高达 10(-3)M 的浓度下不会收缩胃底。相比之下，PGI(2)类似物依洛前列素和贝前列素引起胃底的浓度依赖性收缩。在高浓度（10(-4)M）下观察到对曲前列素的收缩。所有 PGI(2)类似物的收缩均通过激活 EP(3)受体介导，尽管 EP(1)受体也有助于依洛前列素和贝前列素对胃底的收缩。IP 受体拮抗剂不影响反应。口服塞来昔帕在体内对胃功能没有显著影响，如胃排空和肠道转运的速度，而贝前列素则减缓胃肠道转运。塞来昔帕和 ACT-333679 对 IP 受体的高功能选择性排除了对胃平滑肌的刺激作用，这可能有助于最大程度地减少恶心和呕吐等胃部副作用。
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