米非司酮的抗糖皮质激素作用

米非司酮除呈现抗孕激素样作用外,还具有抗糖皮质激素样作用,近年来临床上开始应用于治疗糖皮质激素依赖性内分泌疾病和肿瘤。本文就米非司酮抗糖皮质激素的作用机制和研究进展作一简要综述。     

靶向核受体的抗前列腺癌小分子药物研发新进展

作为全球男性第二大常见癌症,前列腺癌严重威胁着人类健康。在前列腺癌发病过程中,雄激素受体（androgen receptor,AR）起着关键作用,糖皮质激素受体（glucocorticoid receptor,GR）也参与调节部分AR通路下游基因,因此,阻断AR和GR信号通路是前列腺癌治疗的重要策略。综述从核受体AR和GR的结构特征和生物学功能出发,从药物化学角度系统介绍了近5年来靶向核受体的抗前列腺癌药物研发新进展,包括雄激素竞争性AR拮抗剂、雄激素非竞争性AR拮抗剂、AR降解剂、GR拮抗剂和AR/GR双重拮抗剂等,为去势抵抗性前列腺癌的治疗提供新思路。     

糖皮质激素受体介导的胰岛素抵抗及其拮抗剂研究进展

糖皮质激素（GC）是维持机体能量代谢平衡的重要激素之一：GC作用于靶组织，不仅有赖于循环中的GC浓度，还与糖皮质激素受体（GR）的表达相关：外源性及内源性的GC水平升高均会导致机体出现胰岛素抵抗以及与之紧密相关的多种代谢综合征症候，如血脂障碍、内脏性肥胖和高血压。本文对近年来GR介导的胰岛素抵抗及其受体拮抗剂的研究进展进行综述。     

人体内皮素诱导的血管收缩仅由ETA受体介异吗？

由于内皮素（ＥＴ）是有效的血管收缩剂，因此阻断ＥＴ受体可导致血管舒张，具有治疗意义。ＥＴ受体分为ＥＴＡ和ＥＴＢ两种亚型，它们的分布和作用均有所差别。研究证明人类血管收缩主要通过ＥＴＡ受体介导，因此，ＥＴＡ受体选择性结抗剂可避免非选择性拮抗剂的副作用。     

新型抗抑郁药物的研究进展

近年来对抑郁症发病机制和药物治疗靶标的研究取得了很大进展,围绕神经可塑性、神经发生、下丘脑-垂体-肾上腺(HPA)轴等后续神经系统适应性改变以及免疫系统变化,确定了谷氨酸受体、神经肽受体、糖皮质激素受体、褪黑激素受体和细胞因子受体等抗抑郁药物作用的新靶标。目前,已发现大量具有抗抑郁作用的新化合物,褪黑激素受体激动剂阿戈美拉丁、促肾上腺皮质激素释放激素受体拮抗剂喹硫平已经上市,神经激肽2受体拮抗剂沙瑞度坦、糖皮质激素受体拮抗剂米非司酮正在进行Ⅲ期临床研究,10余个药物进入临床研究阶段。本文对近5年新型抗抑郁药物的研究进展进行简要综述。     

内皮素受体拮抗剂治疗肺动脉高压的临床应用进展

内皮素（ET）-1是强有力的内源性血管收缩剂，在肺动脉高压的发病机制中发挥重要作用。ET受体分为两种类型：ETA和ETB。本文综述近年来非选择性ET受体拮抗剂和选择性ETA受体拮抗剂治疗肺动脉高压的临床应用进展。证明ET受体拮抗剂可以改善肺动脉高压患者的运动耐量，降低肺血管阻力，增加心输出量，改善心功能。其主要副作用是血清转氨酶增高。     

人体内皮素诱导的血管收缩仅由ET_A受体介导吗?

由于内皮素（ET）是有效的血管收缩剂，因此阻断ET受体可导致血管舒张，具有治疗意义。ET受体分为ET_A和ET_B两种亚型，它们的分布和作用均有所差别。研究证明人类血管收缩主要通过ET_A受体介导，因此，ET_A受体选择性拮抗剂可避免非选择性拮抗剂的副作用。     

糖皮质激素在炎症调节中的作用

糖皮质激素作为一种重要的肾上腺皮质激素,是临床常用的抗炎药物。对其抗炎机制的探讨已经深入到分子水平。该药主要从基因水平发挥作用,经直接和间接途径抑制炎性因子的合成、转录。近年来的许多报道证明,糖皮质激素还具有促炎作用,在外循环中,其作用方式与浓度、给药时间和机体免疫系统状态密切相关,呈现低浓度促炎、高浓度抗炎的复杂模式,对糖皮质激素在炎症调节中的具体作用和机制有待进一步研究。     

以血管紧张素受体为靶点的药物研究进展

血管紧张素Ⅱ受体共有4种亚型（ATI、AT2、AT3和AT4）.血管紧张素Ⅱ受体拈抗剂是临床上常用的高血压治疗药物,以ATl受体拮抗剂和AT2受体拮抗剂应用较多。近年来,随着对血管紧张素Ⅱ受体拮抗剂研究的深入,涌现出诸多具有良好药理活性的选择性ATl受体拮抗剂、双重作用靶点的非选择性ATl受体拮抗剂和选择性AT2受体拮抗剂。本文对近年来报道的血管紧张素Ⅱ受体拮抗剂进行简要综述。     

内皮素受体拮抗剂治疗心血管疾病研究进展

内皮素(ET)家族包括ET-1，ET-2和ET-3。ET-1通过与血管平滑肌细胞上的特异受体结合而产生血管收缩和细胞增殖效应，其异常表达参与了多种心血管疾病如慢性心衰、高血压、肾衰、肺动脉高压、脑血管痉挛等的病理机制。ET受体包括ETA和ETB2种亚型。动物实验和临床研究表明，非选择性ETA/B拮抗剂和选择性ETA拮抗剂对多种心血管疾病有较好的治疗作用。ET及其受体拮抗剂所具有的广泛的生物学效应和独特的作用机制，为临床治疗相关疾病提供了新途径。     

Glucocorticoid receptor antagonists

This review covers recent progress in the discovery of selective glucocorticoid receptor (GR) antagonists. Potential therapeutic applications of selective GR antagonists are described including the pharmacological rationale and, in some cases, clinical evidence that underlies these proposed uses. Disease areas that are discussed are Cushing's syndrome, psychotic depression, diabetes, obesity, Alzheimer's disease, neuropathic pain, drug abuse, and glaucoma. Methods for evaluating GR antagonist properties (binding, functional, and in vivo assays) are briefly covered. Early research on steroidal ligands which led to the identification of the non-selective GR antagonist RU-486 (mifepristone) and the GR-selective steroid RU-43044 is reviewed as is subsequent work on related steroidal compounds. Structure activity relationships (SAR) of nonsteroidal GR antagonists from the following structural classes are presented: octahydrophenanthrenes, spirocyclic dihydropyridines, triphenylmethanes and diaryl ethers, chromenes, dibenzyl anilines, dihydroisoquinolines, pyrimidinediones, azadecalins, and aryl pyrazolo azadecalins.     

Effect of chronic administration of selective glucocorticoid receptor antagonists on the rat hypothalamic-pituitary-adrenocortical axis.

The effects of the selective glucocorticoid receptor (GR) antagonists ORG 34850, ORG 34116, and ORG 34517 on the rat hypothalamic-pituitary-adrenocortical (HPA) system were investigated. To assess the potency of the compounds to occupy GR in the brain and pituitary, we applied a single acute subcutaneous (s.c.) injection (10 mg/kg). ORG 34517 was most potent to occupy GR in the anterior pituitary and distinct brain areas, whereas all compounds were unable to occupy mineralocorticoid receptor (MR). Chronic administration of ORG 34850, ORG 34116, and ORG 34517 (20 mg/kg/day) for 1, 3, and 5 weeks resulted only in minor changes in brain GR levels. However, profound increases of hippocampal MR were observed virtually at all time points. Treatment with ORG 34850 and ORG 34116 elicited episodic increases in HPA axis activity, whereas ORG 34517 did not cause any changes in HPA activity. Thus, the GR antagonists exert distinct effects on the HPA axis, which may be pertinent for the proposed antidepressant activity of these compounds.     

Discovery of potent,nonsteroidal, and highly selective glucocorticoid receptor antagonists

An approach to the computer-assisted, pharmacophore design of nonsteroidal templates for the glucocorticoid receptor (GR) that contained an element of pseudo-C2 symmetry was developed. The enatiomer of the initial design, 1Ra, and not the designed molecule, 1S, showed the desired ligand binding to the GR. The pseudo-C2 symmetry of the template allowed for rapid improvements in GR activity resulting in potent, selective, nonsteroidal GR antagonists, CP-394531 and CP-409069.     

Endogenous modulation of excitatory amino acid responsiveness by tachykinin NK1 and NK2 receptors in the rat spinal cord.

1. The effects of selective tachykinin (neurokinin, NK) NK1 and NK2 receptor antagonists have been examined on spinal neurones in alpha-chloralose anaesthetized, spinalized rats. They were tested for effects on responses both to excitatory amino acids (EAA) and to noxious heat stimuli. They were also tested for their ability to reverse the actions of selective NK agonists. 2. The NK1-selective antagonists GR82334 (peptide) and CP-99,994 (non-peptide), when applied by microiontophoresis, both reduced responses to kainate > AMPA > NMDA. Intravenous CP-99,994 (3 mg kg-1) also reduced responses to kainate but had inconsistent effects on nociceptive responses. 3. GR82334, applied microiontophoretically, reduced the enhancement by the selective NK1 agonist, GR73632 of both responses to EAAs and background activity. Systemic CP-99,994 (< or = 10 mg kg-1) failed to reverse the effects of GR73632. 4. The selective peptide NK2 antagonist, GR103537, had no consistent effects on responses to EAAs when applied by iontophoresis. In contrast, the non-peptide NK2 antagonist, GR159897, administered systemically (0.5-2 mg kg-1, i.v.) enhanced responses to kainate (but not NMDA); responses to noxious heat were enhanced only weakly. 5. Iontophoretically-administered GR103537 attenuated the effects of the NK2 agonist GR64349, which selectively reduced responses to kainate compared to those to NMDA. Systemically administered GR159897 (< or = 2 mg kg-1, i.v.) caused little antagonism of the effects of GR64349. 6. The data indicate that under these conditions the non-peptide antagonists are not reliable at reversing the actions of selective NK agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dissociated nonsteroidal glucocorticoid receptor modulators; discovery of the agonist trigger in a tetrahydronaphthalene-benzoxazine series

The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.     

Characterization of steroid hormone receptor activities in 100 hydroxylated polychlorinated biphenyls, including congeners identified in humans

Hydroxylated polychlorinated biphenyls (OH-PCBs), major metabolites of PCBs, have been reported to act as estrogen receptor α (ERα) agonists or antagonists. However, little concern has been paid to the ability of OH-PCBs to interfere with other steroid hormone receptors such as ERβ, androgen receptor (AR) or glucocorticoid receptor (GR). In this study, we characterized the agonistic and antagonistic activities of available 100 OH-PCBs (39 ortho-, 24 meta-, and 37 para-OH compounds), including some congeners identified in humans, against human ERα/β, AR, and GR using in vitro reporter gene assays. In the ERα assay, 45 and 9 of the 100 OH-PCBs tested showed agonistic and antagonistic activities, respectively. In the ERβ assay, 45 and 6 compounds showed agonistic and antagonistic activities, respectively. In the AR and GR assays, although none of the compounds tested showed agonistic activity, 83 and 30 of the 100 OH-PCBs showed antagonistic activity, respectively. These AR and/or GR antagonistic compounds had various patterns of substituent in the structure, while relatively potent ERα/β agonistic and antagonistic compounds possessed para- and ortho-OH structures, respectively. Three OH-PCBs, predominantly identified in human tissues, showed little ERα/β or AR activities, apart from the weak ERα and/or GR antagonistic activity observed in 4-OH-CB107 and 4-OH-CB187. Taken together, these results suggest that a large number of OH-PCBs might act as agonists and/or antagonists against ERα/β, AR and GR.     

The 5-HT3 receptor antagonists ICS 205-930 and GR38032F, putative anxiolytic drugs, differ from diazepam in their pharmacological profile

The pharmacological profile of the two 5-HT(3) (5-hydroxytryptamine) receptor antagonists, the putative anxiolytics ICS 205-930 and GR38032F was compared with that of diazepam in four standard behavioural tests in rats. All the investigated drugs induced an anxiolytic effect in the passive avoidance test, having reduced the latency to re-enter the chamber previously associated with an inescapable footshock, and increased the time spent in that chamber. On the basis of the lowest effective dose, both ICS 205-930 and GR38032F were about 20 times more potent than diazepam, though the anxiolytic activity of either 5- HT(3) receptor antagonist was confined to a narrow dose range (ICS 205-930: 93.7-187.5 μg/ kg, GR38032F: 125-375 μg/kg), their higher doses having been ineffective. The anxiolytic effect of diazepam, but not of ICS 205-930, was abolished by flumazenil. In contrast to diazepam, neither ICS 205-930 nor GR38032F-both given in doses up to 20 mg/kg-showed any activity in the pentylenetetrazol-induced seizures, open field, and rota-rod tests. These results suggest that the 5-HT(3) receptor antagonists may represent a new class of anxiolytic drugs devoid of anticonvulsant, sedative or muscle-relaxant properties, and that their anxi olytic activity is not mediated by benzodiazepine receptors.     

The selective tachykinin neurokinin 1 (NK1) receptor antagonist, GR 205,171, stereospecifically inhibits light-induced phase advances of hamster circadian activity rhythms

Circadian rhythms in mammals are generated by master pacemaker cells located within the suprachiasmatic nucleus of the hypothalamus. In hamsters, the suprachiasmatic nucleus contains a small collection of cells immunoreactive for substance P, the endogenous ligand of tachykinin neurokinin 1 (NK1) receptors. In addition, two other nuclei which form part of the circadian system, the intergeniculate leaflet of the thalamus and the raphe nuclei, also contain fibers and/or cell bodies immunoreactive for substance P. In light of these observations, we evaluated the influence of the selective tachykinin NK1 receptor antagonist, GR 205,171, upon circadian activity rhythms in the hamster. Systemic injection of GR 205,171 dose-dependently (2.5-40.0 mg/kg, i.p.) inhibited light-induced phase advances in hamster circadian wheel running activity rhythms by approximately 50%. In contrast, GR 226,206, the less active enantiomer of GR 205,171, failed to affect light-induced phase advances. In addition, we examined the potential ability of GR 205,171 to induce non-photic phase shifts in hamster wheel running rhythms when injected at mid-day to late night circadian times. However, GR 205,171 (40 mg/kg) did not elicit non-photic phase shifts at these times indicating that tachykinin NK1 receptor antagonists are only effective when a light stimulus is applied to the pacemaker. Although GR 205,171 may, in theory, activate several sites within the circadian system, we suggest that GR 205,171 acts in the raphe nuclei to increase inhibitory serotonergic input to pacemaker cells in the suprachiasmatic nuclei, thereby suppressing photic modulation of the pacemaker. These findings have important implications for the use of tachykinin NK1 receptor antagonists in the treatment of depression and other central nervous system disorders.