A PHARMACOLOGICAL PROFILE OF THE NOVEL, PERIPHERALLY-SELECTIVE KAPPA-OPIOID RECEPTOR AGONIST, EMD-61753
A PHARMACOLOGICAL PROFILE OF THE NOVEL, PERIPHERALLY-SELECTIVE KAPPA-OPIOID RECEPTOR AGONIST, EMD-61753
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DOI：
10.1111/j.1476-5381.1994.tb17142.x
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发表时间：
1994-12-01
影响因子：
7.3
通讯作者：
SEYFRIED, CA
中科院分区：
文献类型：
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作者：
BARBER, A;BARTOSZYK, GD;SEYFRIED, CA
1比较新型二芳基乙酰胺类阿片受体激动剂EMD 61753与ICI 197067(中枢作用Kappa激动剂)和ICI 204448(外周选择性Kappa激动剂)的药理性质。2 EMD 61753结合具有高亲和力(IC505.6 nm)和选择性(Kappa：Mu：Delta：Sigma结合比1：536：125：>)；对kappa-阿片受体(兔输精管制剂)是一种完全有效的(IC5054.5 nM)激动剂。3全身应用的[C-14]-EMD 61753在肺、肝脏、肾上腺和肾脏中浓度很高。在整个大脑中检测到的放射性要少得多，而且这种放射性集中在脉络丛中的脑室区域。EMD 61753对中枢神经系统的渗透性较差。4在中枢活性的药理实验中，EMD 61753的药效较弱。该化合物仅在30 mg kg(-1)，S.C.，(0.1，1.0，10 mg kg(-1)，S.C.，1.0，10,100 mg kg(-1)，P.C.，无效)剂量下逆转氟哌啶醇诱导的DOPA在大鼠伏隔核内的蓄积。EMD 61753可延长己巴比妥钠诱导的小鼠睡眠时间，其阈值剂量分别为10 mg·kg~(-1)，S.C.和100 mg·kg~(-1)，而EMD_(61753)可使大鼠旋转试验中的运动能力下降，其ID_(50)值为453 mg·kg~(-1)；第二阶段ID50 0.26 mg kg(-1)，S.C.，3.5 mg kg(-1)，P.O.)小鼠腹壁收缩试验(ID50大鼠3.2 mg kg(-1)，S.C.，250 mg kg(-1)，P.O.在正常条件下的大鼠压力测试中，EMD 61753是不活跃的，或仅是弱有效的。但在角叉菜胶致痛敏后，该化合物具有剂量依赖性(给药后ID50分别为0.08 mg kg(-1)和6.9 mg kg(-1)，P.O.；预防性给药后ID50分别为0.2 mg kg(-1)和3.1 mg kg(-1)，P.O.)和纳洛酮可逆性镇痛作用。全身应用(50 mg·kg~(-1)，P.O.)在痛觉过敏压力实验中，阿片受体拮抗剂去甲肾上腺素(100mU G)可完全抑制炎症组织中的EMD 61753，这表明这种阿片效应是外周介导的。6全身应用EMD 61753(ID50值分别为3.7mgkg(-1)，S.C.和35.8mgkg(-1)，P.O.)可剂量依赖地抑制大鼠隐神经逆行电刺激引起的皮肤血浆蛋白外溢，这种作用可被去甲肾上腺素(50mU G)足底注射完全拮抗。足底注射EMD 61753对足底注射P物质(10 MU G)引起的渗出无明显影响，但对非水化大鼠皮下注射EMD 61753.7产生剂量依赖性利尿作用，对生理盐水负荷大鼠静脉注射前列腺素引起的平均动脉压下降无明显影响。预先给予EMD 61753(10 mg·kg~(-1)，P.O.)不抑制花生四烯酸的应用。因此，通过抑制环氧合酶活性来阻断前列腺素合成并不有助于EMD 61753及其代谢物的体内效应。9因此，目前的实验表明EMD 61753是一种有效的、选择性的和口服有效的全阿片受体激动剂，其穿透血脑屏障的能力有限，并引发中枢介导的镇静、假定的厌恶、利尿和抗伤害感受。系统应用的EMD 61753对痛觉过敏性痛觉伤害和神经源性炎症的抑制作用是外周介导的，可能是通过感觉神经纤维末端的阿片受体介导的。
1 The pharmacological properties of the novel diarylacetamide kappa-opioid receptor agonist, EMD 61753, have been compared with those of ICI 197067 (a centrally-acting kappa agonist) and ICI 204448 (a peripherally-selective kappa agonist).2 EMD 61753 binds with high affinity (IC50 5.6 nM) and selectivity (kappa:mu:delta:sigma binding ratio 1:536: 125:> 1,786) to kappa-opioid receptors and is a full and potent (IC50 54.5 nM) agonist in an in vitro assay for kappa-opioid receptors (rabbit vas deferens preparation).3 Systemically-applied [C-14]-EMD 61753 is found in high concentrations in the lungs, liver, adrenal glands and kidneys. Considerably less radioactivity is detected in the whole brain, and this radioactivity is concentrated in the region of the cerebral ventricles in the choroid plexuses. EMD 61753 penetrates only poorly into the CNS.4 EMD 61753 was weakly effective in pharmacological tests of central activity. This compound reversed haloperidolol-induced DOPA accumulation in the nucleus accumbens of the rat only at a dose of 30 mg kg(-1), s.c., (doses of 0.1, 1.0 and 10 mg kg(-1), s.c., and 1.0, 10 and 100 mg kg(-1), p.o., were inactive). Hexobarbitone-induced sleeping in mice was prolonged by EMD 61753 at threshold doses of 10 mg kg(-1), s.c., and 100 mg kg(-1), p.o., whereas the motor performance of rats in the rotarod test was impaired by EMD 61753 with an ID50 value of 453 mg kg(-1), s.c.5 EMD 61753 produced dose-dependent, naloxone-reversible antinociception in the mouse formalin test (1st phase ID50 1.9 mg kg(-1), s.c., and 10.4 mg kg(-1), p.o.; 2nd phase ID50 0.26 mg kg(-1), s.c., and 3.5 mg kg(-1), p.o.) and rodent abdominal constriction test (IDS, mouse 1.75 mg kg(-1), s.c., and 8.4 mg kg(-1), p.o.; ID50 rat 3.2 mg kg(-1), s.c., and 250 mg kg(-1), p.o.). EMD 61753 was inactive, or only weakly effective, in the rat pressure test under normalgesic conditions. After the induction of hyperalgesia with carrageenin, however, this compound elicited potent, dose-dependent (ID50 0.08 mg kg(-1), s.c., and 6.9 mg kg(-1), p.o., after remedial application, and 0.2 mg kg(-1), s.c., and 3.1 mg kg(-1), p.o., after prophylactic application) and naloxone-reversible antinociception. The antinociceptive action of systemically-applied (50 mg kg(-1), p.o.) EMD 61753 in the hyperalgesic pressure test was completely inhibited by injection of the kappa-opioid antagonist norbinaltorphimine (100 mu g) into the inflamed tissue, a result which indicates that this opioid effect is mediated peripherally.6 Cutaneous plasma protein extravasation produced by antidromic electrical stimulation of the rat saphenous nerve was dose-dependently inhibited by systemically-applied EMD 61753 (ID50 values 3.7 mg kg(-1), s.c., and 35.8 mg kg(-1), p.o.), and this effect was completely antagonized by intraplantar application of norbinaltorphimine (50 mu g). Extravasation elicited by the intraplantar application of substance P (10 mu g) was not influenced by the administration of EMD 61753.7 EMD 61753 produced dose-dependent diuresis in non-hydrated rats at doses of and above 1.0 mg kg(-1), s.c., and 10 mg kg(-1), p.o., and in saline-loaded rats at doses of and above 10 mg kg(-1), s.c., and 30 mg kg(-1), p.o.8 The prostaglandin-mediated fall in mean arterial blood pressure elicited in anaesthetized rats by i.v. application of arachidonic acid was not inhibited by prior treatment with EMD 61753 (10 mg kg(-1), p.o.). Thus, a blockade of prostaglandin synthesis via inhibition of cyclo-oxygenase activity does not contribute to the in vivo effects of EMD 61753 and its metabolites.9 The present experiments therefore indicate that EMD 61753 is a potent, selective and orally-effective full kappa-opioid receptor agonist which has a limited ability to penetrate the blood-brain barrier and elicit centrally-mediated sedation, putative aversion, diuresis, and antinociception. The inhibitory actions of systemically-applied EMD 61753 against hyperalgesic pressure nociception and neurogenic inflammation are mediated peripherally, probably by opioid receptors on the endings of sensory nerve fibres.