Gully D, Labeeuw B, Boigegrain R, Oury-Donat F, Bachy A, Poncelet M, Steinberg R, Suaud-Chagny M F, Santucci V, Vita N, Pecceu F, Labbé-Jullié C, Kitabgi P, Soubrié P, Le Fur G, Maffrand J P
Sanofi Recherche, Toulouse, France.
J Pharmacol Exp Ther. 1997 Feb;280(2):802-12.
SR 142948A, 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylc arbamoyl)-2-isopropylphenyl)-1H-pyrazole3-carbonyl]amino] adamantane-2-carboxylic acid, hydrochloride, a new and extremely potent neurotensin (NT) receptor antagonist, has been characterized in comparison with SR 48692. This selective compound possesses nanomolar affinities for NT receptors, recognizes the two binding sites described for the NT receptor and fully displaces [3H]SR 48692 specific binding. SR 142948A antagonizes the classical in vitro NT effects, i.e., inositol monophosphate formation in HT 29 cells (IC50 = 3.9 nM) or intracellular calcium mobilization in Chinese hamster ovary cells transfected with the human receptor. It dose-dependently (0.04-640 x 10(-3) mg/kg p.o.) inhibits the turning behavior induced by unilateral intrastriatal injection of NT in mice, with the biphasic profile previously seen for SR 48692. At 0.1 mg/kg (i.p.), it completely antagonizes NT-evoked acetylcholine release in the rat striatum. In contrast to SR 48692, SR 142948A (p.o.) blocks both hypothermia and analgesia induced by i.c.v. injection of NT (mice and/or rats) but is unable to modify the dopamine release evoked by NT injection into the ventral tegmental area. In summary, SR 142948A retains the properties of the lead compound SR 48692 (no intrinsic agonist activity, oral bioavailability, long duration of action and good brain access), reveals a wider spectrum of activity than SR 48692 (probably due to the inhibition of NT receptor subtypes) and represents an additional tool for further exploration of the therapeutic potential of this class of compounds.
SR 142948A，即2-[[5-(2,6-二甲氧基苯基)-1-(4-(N-(3-二甲基氨基丙基)-N-甲基氨基甲酰基)-2-异丙基苯基)-1H-吡唑-3-羰基]氨基]金刚烷-2-羧酸盐酸盐，是一种新型且强效的神经降压素（NT）受体拮抗剂，已与SR 48692进行了对比研究。这种选择性化合物对NT受体具有纳摩尔级亲和力，识别出为NT受体描述的两个结合位点，并能完全取代[3H]SR 48692特异性结合。SR 142948A拮抗经典的体外NT效应，即在HT 29细胞中肌醇单磷酸的形成（IC50 = 3.9 nM）或在转染了人受体的中国仓鼠卵巢细胞中的细胞内钙动员。它以剂量依赖性方式（0.04 - 640×10(-3) mg/kg口服）抑制小鼠单侧纹状体内注射NT诱导的转向行为，呈现出先前在SR 48692中观察到的双相特征。在0.1 mg/kg（腹腔注射）时，它能完全拮抗NT诱发的大鼠纹状体中乙酰胆碱的释放。与SR 48692不同，SR 142948A（口服）能阻断脑室内注射NT（小鼠和/或大鼠）诱导的体温过低和镇痛，但不能改变向腹侧被盖区注射NT所诱发的多巴胺释放。总之，SR 142948A保留了先导化合物SR 48692的特性（无内在激动剂活性、口服生物利用度、长效作用和良好的脑内通透性），显示出比SR 48692更广泛的活性谱（可能是由于对NT受体亚型的抑制），并且是进一步探索这类化合物治疗潜力的又一工具。
