Chang K J, Rigdon G C, Howard J L, McNutt R W
Division of Cell Biology, Burroughs Wellcome Co., Research Triangle Park, North Carolina.
J Pharmacol Exp Ther. 1993 Nov;267(2):852-7.
Four different opioid receptor binding assays and three different isolated tissue studies were used to screen for delta receptor-selective nonpeptidic compounds. (+/-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-Allyl-2,5- dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (BW373U86) was a potent delta receptor-selective ligand in receptor binding assays. The Ki values were 1.8 +/- 0.4, 15 +/- 3, 85 +/- 4 and 34 +/- 3 nM for delta, mu, epsilon and kappa receptor binding sites, respectively. BW373U86 inhibited electrically evoked muscle contraction of mouse vas deferens with an ED50 value of 0.2 +/- 0.06 nM. This inhibitory effect of BW373U86 was antagonized by the delta receptor-selective antagonist naltrindole in a competitive manner: the Schild plot indicated a slope of 1 and a pA2 value of 9.43 (Ke = 3.7 x 10(-10) M), which is consistent with the high affinity of naltrindole in delta receptors. BW373U86 did not interact significantly with other receptors. BW373U86 inhibited the acoustic startle reflex after subcutaneous administration from 0.2- to 2-mg/kg doses in rats, and this inhibition was blocked by naltrindole. BW373U86 also induced a dose-dependent increase of locomotor activity in rats at similar doses. This effect was inhibited by naltrindole. These data suggest that BW373U86 is a potent and selective nonpeptidic delta agonist, and it elicits distinct in vivo pharmacological activities.
采用四种不同的阿片受体结合试验和三种不同的离体组织研究来筛选δ受体选择性非肽类化合物。(+/-)-4-((α-R*)-α-((2S*,5R*)-4-烯丙基-2,5-二甲基-1-哌嗪基)-3-羟基苄基)-N,N-二乙基苯甲酰胺（BW373U86）在受体结合试验中是一种有效的δ受体选择性配体。δ、μ、ε和κ受体结合位点的Ki值分别为1.8±0.4、15±3、85±4和34±3 nM。BW373U86抑制小鼠输精管电诱发的肌肉收缩，ED50值为0.2±0.06 nM。BW373U86的这种抑制作用被δ受体选择性拮抗剂纳曲吲哚以竞争性方式拮抗：Schild图显示斜率为1，pA2值为9.43（Ke = 3.7×10(-10) M），这与纳曲吲哚在δ受体中的高亲和力一致。BW373U86与其他受体无明显相互作用。BW373U86皮下给药0.2 - 2 mg/kg剂量可抑制大鼠的听觉惊吓反射，且这种抑制作用被纳曲吲哚阻断。BW373U86在相似剂量下也可诱导大鼠运动活性呈剂量依赖性增加。这种作用被纳曲吲哚抑制。这些数据表明BW373U86是一种强效且选择性的非肽类δ激动剂，并且它能引发不同的体内药理活性。
