Serradeil-Le Gal Claudine, Valette Gérard, Foulon Loïc, Germain Guy, Advenier Charles, Naline Emmanuel, Bardou Marc, Martinolle Jean-Pierre, Pouzet Brigitte, Raufaste Danielle, Garcia Corinne, Double-Cazanave Eléonore, Pauly Maxime, Pascal Marc, Barbier Alain, Scatton Bernard, Maffrand Jean-Pierre, Le Fur Gérard
Exploratory Research Department, Sanofi-Synthélabo Recherche, 195 route d'Espagne, 31036 Toulouse Cedex, France.
J Pharmacol Exp Ther. 2004 Apr;309(1):414-24. doi: 10.1124/jpet.103.061200. Epub 2004 Jan 13.
4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide, hydrochloride (SSR126768A), a new potent and selective, orally active oxytocin (OT) receptor antagonist was characterized in several biochemical and pharmacological models. In binding studies, SSR126768A showed nanomolar affinity for rat and human recombinant and native OT receptors (K(i) = 0.44 nM) and exhibited much lower affinity for V(1a), V(1b), and V(2) receptors. In addition, it did not interact with a large number of other receptors, enzymes, and ion channels (1 microM). In autoradiographic experiments performed on at-term human pregnant uterus sections, SSR126768A dose dependently displaced [I(125)]d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8) (125)I-Tyr-NH(2)(9)]VT in situ labeling to OT receptors highly expressed in these tissues. In functional studies, SSR126768A behaved as a full antagonist and potently antagonized OT-induced intracellular Ca(2+) increase (K(i) = 0.50 nM) and prostaglandin release (K(i) = 0.45 nM) in human uterine smooth muscle cells. In rat isolated myometrium, OT-induced uterine contractions were competitively antagonized by SSR126768A (pA(2) = 8.47). Similarly, in human pregnant myometrial strips, SSR126768A inhibited the contractile uterine response to OT. In conscious telemetrated rats, oral administration of SSR126768A (1-10 mg/kg) produced a competitive inhibition of the dose response to OT on uterine contractions up to 24 h at 3 mg/kg p.o.; no tachyphylaxis was observed after 4-day repeated treatment. Finally, SSR126768A (30 mg/kg p.o.) significantly delayed parturition in pregnant rats in labor similar to ritodrine (10 mg/kg p.o.). Thus, SSR126768A is a potent, highly selective, orally active OT receptor antagonist with a long duration of action. This molecule could find therapeutic application as a tocolytic agent for acute and chronic oral management of preterm labor.
4-氯-3-[(3R)-(+)-5-氯-1-(2,4-二甲氧基苄基)-3-甲基-2-氧代-2,3-二氢-1H-吲哚-3-基]-N-乙基-N-(3-吡啶基甲基)苯甲酰胺盐酸盐(SSR126768A)是一种新型强效、选择性、口服活性的催产素(OT)受体拮抗剂，已在多种生化和药理模型中得到表征。在结合研究中，SSR126768A对大鼠和人类重组及天然OT受体表现出纳摩尔亲和力(Ki = 0.44 nM)，对V1a、V1b和V2受体的亲和力则低得多。此外，它不与大量其他受体、酶和离子通道相互作用(1 μM)。在对足月人类妊娠子宫切片进行的放射自显影实验中，SSR126768A剂量依赖性地取代了[I125]d(CH2)5[Tyr(Me)2, Thr4, Orn8 (125)I-Tyr-NH2(9)]VT在原位标记到这些组织中高表达的OT受体上。在功能研究中，SSR126768A表现为完全拮抗剂，在人子宫平滑肌细胞中有效拮抗OT诱导的细胞内Ca2+增加(Ki = 0.50 nM)和前列腺素释放(Ki = 0.45 nM)。在大鼠离体子宫肌层中，OT诱导的子宫收缩被SSR126768A竞争性拮抗(pA2 = 8.47)。同样，在人妊娠子宫肌条中，SSR126768A抑制子宫对OT的收缩反应。在清醒遥测大鼠中，口服给予SSR126768A(1 - 10 mg/kg)对OT引起的子宫收缩剂量反应产生竞争性抑制，在3 mg/kg口服时长达24小时；4天重复给药后未观察到快速耐受性。最后，SSR126768A(30 mg/kg口服)与利托君(10 mg/kg口服)相似，显著延迟了临产妊娠大鼠的分娩。因此，SSR126768A是一种强效、高度选择性、口服活性的OT受体拮抗剂，作用持续时间长。该分子可作为治疗剂用于早产的急性和慢性口服管理。
