ς1 Recognition Sites in Rabbit Iris-Ciliary Body: Topical ς1-Site Agonists Lower Intraocular Pressure
ς1 Recognition Sites in Rabbit Iris-Ciliary Body: Topical ς1-Site Agonists Lower Intraocular Pressure
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发表时间：
1999-06
影响因子：
3.5
通讯作者：
C. Bucolo;G. Campana;R. Toro;S. Cacciaguerra;S. Spampinato
中科院分区：
文献类型：
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作者：
C. Bucolo;G. Campana;R. Toro;S. Cacciaguerra;S. Spampinato
在这项研究中，我们检查了存在的虹膜睫状体的受体结合和研究其对白化病兔眼内压（IOP）的影响，EST 1和EST 2网站。虹膜-睫状体具有与β 1位点激动剂[3 H]（+）-喷他佐辛（Kd = 4.6 nM; B max = 212 fmol/mg蛋白质）结合的位点和用[3 H] 1，3-二-邻甲苯基胍（DTG）标记的β 2位点（Kd = 8.2 nM; B max = 1120 fmol/mg蛋白质）。在竞争结合研究中，（+）-喷他佐辛和β-内酰胺酶拮抗剂NE-100对β-内酰胺酶1位点表现出高亲和力（Ki分别为2.1和2.4 nM），而（+）- N -烯丙基去甲唑辛（NANM）的亲和力较低（Ki = 178 nM）.单侧局部（+）-喷他佐辛（0.01-0.1%）可使眼压正常的兔和高眼压的α-糜蛋白酶模型的IOP显著降低，且与剂量相关。（+）-NANM的效力低于（+）-喷他佐辛。这两种化合物都没有改变对侧眼的IOP，它们的消肿活性被NE-100阻断，NE-100本身对IOP没有影响。（-）-喷他佐辛、（-）-NANM和DTG对IOP无影响。DTG阻止了（+）-喷他佐辛的抑制作用，提示其作为β 1位点拮抗剂。β-位点配体不影响瞳孔直径或引起眼部炎症。局部[3 H]（+）-喷他佐辛在30分钟内到达眼内组织，其在虹膜-睫状体和视网膜中的摄取通过用NE-100局部预处理显著降低，如受体特异性试剂所预期的。反相HPLC证实虹膜睫状体匀浆中存在完整的（+）-喷他佐辛。ς1-位点激动剂可能提供一类新型药物，可能有效控制高眼压。
In this study, we examined the presence of ς1 and ς2 sites in the rabbit iris-ciliary body by receptor binding and investigated their effects on intraocular pressure (IOP) in albino rabbits. The iris-ciliary body has binding sites for the ς1-site agonist [3H](+)-pentazocine ( K d = 4.6 nM; B max = 212 fmol/mg protein) and ς2 sites labeled with [3H]1,3-di- o -tolylguanidine (DTG) ( K d = 8.2 nM; B max = 1120 fmol/mg protein). In competition binding studies, (+)-pentazocine and the ς antagonist NE-100 displayed high affinity for ς1 sites ( K i = 2.1 and 2.4 nM, respectively), whereas (+)- N -allylnormetazocine (NANM) was less potent ( K i = 178 nM). Unilateral topical (+)-pentazocine (0.01–0.1%) caused a significant dose-related reduction of IOP in ocular normotensive rabbits and in the α-chymotrypsin model of ocular hypertension. (+)-NANM was less potent than (+)-pentazocine. Neither compound altered the IOP of the contralateral eye, and their hypotensive activity was blocked by NE-100 that, by itself, had no effect on IOP. (−)-Pentazocine, (−)-NANM, and DTG had no effect on IOP. DTG prevented the hypotensive effect of (+)-pentazocine, suggesting that it acts as a ς1-site antagonist. ς-Site ligands did not affect pupil diameter or cause ocular inflammation. Topical [3H](+)-pentazocine reaches the intraocular tissues within 30 min, and its uptake in the iris-ciliary body and retina was significantly reduced by topical pretreatment with NE-100, as expected for a receptor-specific agent. Reverse-phase HPLC confirmed the presence of intact (+)-pentazocine in iris-ciliary body homogenates. ς1-Site agonists may offer a novel class of agents potentially effective in the control of ocular hypertension.