Therapeutic potency of pharmacological adenosine receptor agonist/antagonist in angiogenesis,current status and perspectives

Objectives

Adenosine concentration significantly increases in tumour microenvironment contributing to tumorigenic processes including cell proliferation, survival, invasion and of special interest in this review angiogenesis.

Key findings

This review summarizes the role of pharmacological adenosine receptor agonist and antagonist in regulating angiogenesis for a better understanding and hence a better management of angiogenesis‐associated disorders.

Summary

Depending upon the pharmacological characteristics of adenosine receptor subtypes, adenosine elicits anti‐ or pro‐angiogenic responses in stimulated cells. Inhibition of the stimulatory effect of adenosine signalling on angiogenesis using specific pharmacological adenosine receptor agonist, and antagonist is a potentially novel strategy to suppress angiogenesis in tumours.

     

新型多巴胺D2类受体部分激动剂brexpiprazole

在多巴胺D2类受体中,D2受体部分激动剂对中脑边缘通路可产生功能性拮抗作用,能有效的改善精神分裂症因D2过度活动引起的阳性症状;对中脑皮层通路可产生功能性激动作用,可改善D2功能低下所引起的阴性症状、认知损害。brexpiprazole是一种新型多靶点作用机制的用于精神障碍疾病的治疗药物,除主要具备多巴胺D2受体部分激动作用之外,还具备D3受体部分激动作用、5-HT1A部分受体激动作用和5-HT2A部分受体拮抗作用,是针对单胺类神经递质多靶点开发的同时具有抗精神分裂和抗抑郁作用的新药,目前正在进行Ⅲ期临床试验。     

Proteinase‐activated receptor‐2 (PAR2) and mouse osteoblasts: Regulation of cell function and lack of specificity of PAR2‐activating peptides

1. Using synthetic proteinase‐activated receptor‐2 (PAR₂)‐activating peptides (PAR₂APs) corresponding to the tethered ligand domain of the extracellular N‐terminus of PAR₂ to mimic the actions of activating proteinases and using primary cultures of calvarial osteoblasts derived from both wild‐type (WT) and PAR₂‐null (KO) mice, we investigated the potential role of PAR₂ in regulating osteoblast function. 2. Primary calvarial osteoblasts from WT and KO mice were evaluated for their growth kinetics and mineralization in the absence of PAR₂ agonists and for their responses in a variety of functional assays to the PAR₂APs Ser‐Leu‐Ile‐Gly‐Arg‐Leu‐amide (SLIGRL‐NH₂) and 2‐furoyl‐Leu‐Ile‐Gly‐Arg‐Leu‐Orn‐amide (2‐fLIGRLO‐NH₂), as well as to trypsin. 3. In contrast with WT cells, PAR₂‐KO osteoblasts did not exhibit increased collagen Type I mRNA expression in response to SLIGRL‐NH₂. When grown in serum‐containing medium, KO cells increased in number more rapidly than WT cells, an effect that could be attributed to decreased apoptosis rather than increased proliferation. Surprisingly, in both WT and KO osteoblasts, the two PAR₂APs induced mobilization of intracellular calcium stores. Similarly, the PAR₂APs inhibited serum deprivation‐induced apoptosis and parathyroid hormone‐, 1,25‐dihydroxyvitamin D₃‐ or interleukin‐11‐induced mineralization in WT and KO cells. 4. We conclude that PAR₂ plays a role in osteoblast survival and collagen Type I mRNA induction and that osteoblasts can respond to the PAR₂APs via both PAR₂‐dependent and ‐independent mechanisms.     

Lixivaptan: a novel vasopressin receptor antagonist

Arginine vasopressin, also known as antidiuretic hormone, is a neuropeptide that functions in the maintenance of body water homeostasis. Inappropriate secretion of vasopressin has been implicated in the pathophysiology of multiple diseases, including polycystic kidney disease, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and the hyponatremia commonly associated with cirrhosis and congestive heart failure. Vasopressin receptor antagonists are novel agents that block the physiologic actions of vasopressin. Lixivaptan is a vasopressin receptor antagonist with high V2 receptor affinity and is now undergoing Phase III clinical trials. Studies so far have demonstrated that lixivaptan is efficacious in the correction of hyponatremia in SIADH, heart failure and liver cirrhosis with ascites, and few adverse effects have been noted. Thus, lixivaptan remains a promising therapeutic modality for the treatment of multiple diseases and prevention of the associated morbidity and mortality associated with hyponatremia.     

白三烯受体拮抗剂改善哮喘患者炎症及免疫功能的效果分析

目的 分析白三烯受体拮抗剂在哮喘患者中的抗炎、改善免疫功能的效果。方法 选取鼓楼医院2014年8月至12月收治的86例哮喘患者为研究对象,随机分为对照组（43例）和观察组（43例）,对照组采用常规治疗+沙美特罗替卡松粉吸入剂（舒利迭50 μg/250 μg）,观察组在对照组的基础上采用白三烯受体拮抗剂（孟鲁司特钠片）,两组疗程均为14 d。比较两组炎性因子、免疫功能的变化,以评估治疗方案的有效性,同时比较两组的不良反应。结果 观察组的炎性因子如IL-6、TNF-α及CRP较之对照组均有所降低,差异有统计学意义（P<0.05）。观察组的免疫功能指标如CD4⁺、CD4⁺/CD8⁺高于对照组,CD8⁺均低于对照组,差异有统计学意义（P<0.05）。观察组经治疗后的ACT评分较之对照组有所提高,且总有效率也高于对照组,差异有统计学意义（P<0.05）。两组患者在治疗过程中均未出现明显不良反应。结论 白三烯拮抗剂（孟鲁司特）在哮喘治疗中能够发挥抗炎和改善免疫功能的效果,这可能是其提高哮喘治疗效果的重要机制。     

Valsartan: a novel angiotensin Type 1 receptor antagonist

Valsartan is a highly selective, orally available antagonist of the angiotensin Type 1 (AT₁)receptor. It is indicated for treatment of mild to moderate essential hypertension. Experimental studies have confirmed the abolition or attenuation of angiotensin II (AII)-related effects, such as vasoconstriction, cell growth promotion and aldosterone release. In humans, valsartan is rapidly absorbed with maximal plasma concentrations occurring 1 - 2 h after oral administration. The elimination half-life comes to about 7 - 8 h, valsartan is metabolised to a negligible extent and most of the drug is excreted via the faeces. There is no dose adjustment required for patients with a creatinine clearance >> 10 ml/min. The dose should not exceed 80 mg o.d. in patients with hepatic dysfunction, valsartan is not recommended for patients with severe hepatic dysfunction and/or biliary cirrhosis. At present, no clinically relevant pharmacokinetic drug interactions have been observed. Valsartan produces persistent blood pressure reductions in patients with mild to moderate hypertension, the recommended starting dose is 80 mg o.d. If required, the dose may either be increased to 160 mg o.d. or hydrochlorothiazide may be added. In comparison to other antihypertensive drugs valsartan therapy leads to similar blood pressure reductions, while exhibiting a favourable tolerability profile. Preliminary studies suggest beneficial effects in patients with hypertensive end-organ damage such as renal disease and left ventricular hypertrophy. Furthermore, the drug is evaluated for its efficacy in heart failure and patients post-myocardial infarction.     

作用于AT2受体化合物的研究进展

血管紧张素Ⅱ2型受体(angiotensin receptor type 2,AT2R)是血管紧张素Ⅱ (angiotensin Ⅱ,Ang Ⅱ)受体亚型之一,选择性激动或拮抗AT2受体可引起血管舒张、抗细胞增殖、促突起生长、阻断神经元兴奋性等.AT2受体可作为潜在的药物靶标用于心血管疾病、纤维化、炎症、神经元疾病和肿...     

LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B2 receptor

1. In the present paper, we describe the in vitro pharmacological properties of LF 16.0335 (1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichloro-phenyl]sulphonyl] -2(S) - [[4 -[4-(aminoiminomethyl)phenylcarbonyl]piperazin-1-yl]carbonyl]pyrrolidine), a novel and potent nonpeptide antagonist of the human bradykinin (BK) B₂ receptor.
2. LF 16.0335 displaced [³H]-BK binding to membrane preparations from CHO cells expressing the cloned human B₂ receptor, INT 407 cells and human umbilical vein with K_i values of 0.84±0.39 nM, 1.26±0.68 nM and 2.34±0.36 nM, respectively.
3. In saturation binding studies performed in INT 407 cell membranes in the presence or absence of LF 16.0335, B_max values of [³H]-BK were not significantly changed suggesting that LF 16.0335 behaves as a competitive antagonist.
4. LF 16.0335 had no affinity for the cloned human kinin B₁ receptor stably expressed in 293 cells. In addition, this compound at 1 μM did not significantly bind to a range of 40 different membrane receptors and eight ion channels except muscarinic M₂ and M₁ receptors for which an IC₅₀ value of 0.9 and 1 μM was obtained.
5. BK stimulates in a concentration-dependent manner phosphoinositosides (IPs) production in cultured INT 407 cells. Concentration-response-curves to BK were shifted to the right in the presence of LF 16.0335 (0.1 μM) without reduction of the maximum. LF 16.0335 inhibited the concentration-contraction curve to BK in the human umbilical vein giving a pA₂ value of 8.30±0.30 with a Schild plot slope that was not different from unity.
6. These results demonstrate that LF 16.0335 is a potent, selective and competitive antagonist of the human bradykinin B₂ receptor.

     

γ-Mangostin, a novel type of 5-hydroxytryptamine 2A receptor antagonist

γ-Mangostin, purified from the fruit hull of the medicinal plant Garcinia mangostana caused a parallel rightwards shift of the concentration/response curve for the contraction elicited by 5-hydroxytryptamine (5-HT) in the rabbit aorta (pA₂ = 8.2) without affecting the contractile responses to KCl, phenylephrine (α₁) or histamine (H₁). The perfusion pressure response of rat coronary artery to 5-HT (5-HT_2A) was reduced concentration dependently by γ-mangostin (IC₅₀ = 0.32 μM). 5-HT amplified, ADP-induced aggregation of rabbit platelets (5-HT_2A) was inhibited by γ-mangostin (IC₅₀ = 0.29 μM), whereas that induced by thrombin was not affected, nor did γ-mangostin affect 5-HT-induced contraction of the guinea-pig ileum (5-HT₃)in the presence of 5-HT₁, 5-HT₂ and 5-HT₄ receptor antagonists. Furthermore, 5-HT-induced contraction of the rat fundus (5-HT_2B) and 5-HT-induced relaxation of the rabbit aorta in the presence of ketanserin (5-HT₁) and carbachol-induced contraction of the guinea-pig ileum (muscarinic M₃) were not affected by γ-mangostin (5 μM). γ-Mangostin inhibited [³H]spiperone binding to cultured rat aortic myocytes (IC₅₀ = 3.5 nM). The K _d for [³H]spiperone binding was increased by γ-mangostin (3 nM) from 11.7 to 27.4 nM without affecting B _max. These results suggest that γ-mangostin is a novel competitive antagonist, free from a nitrogen atom, for the 5-HT_2A receptors in vascular smooth muscles and platelets. Received: 10 June 1997 / Accepted: 11 September 1997     

Potent antagonists for the human adenosine A2B receptor. Derivatives of the triazolotriazine adenosine receptor antagonist ZM241385 with high affinity

A series of novel and known 5‐substituted 7‐amino‐2‐(2‐furyl)[1,2,4]triazolo[1,5‐a][1,3,5]triazine derivatives were synthesized and tested for adenosine receptor antagonism in radioligand binding assays at all four adenosine receptor subtypes and for inhibition of the agonist‐induced cyclic AMP response at human A_2B receptors. The known potent adenosine A_2A receptor antagonist, 7‐amino‐2‐(2‐furyl)‐5‐[2‐(4‐hydroxyphenyl)ethyl]amino[1,2,4]triazolo[1,5‐a][1,3,5]triazine (ZM241385, K_iA_2A = 1.78 nM) had a K_i value of 16.5 nM at A_2B receptors in radioligand binding studies on Chinese hamster ovary cells expressing A_2B receptors. A pA₂ value of 7.9 was measured for the inhibition of the cyclic AMP response by A_2B receptors induced by 5′‐N‐ethylcarboxamidoadenosine (NECA). In a series of 5‐phenyl(alkyl)amino analogs the 5‐(2‐phenylethyl)amino analog LUF5452 and the 5‐benzylamino analog LUF5451 were both more potent than ZM241385 in the cyclic AMP assay at A_2B receptors. Moreover, K_i values of 9.9 and 7.6 nM were found in binding studies at this receptor subtype, indicating that LUF5451 and LUF5452 are more potent A_2B receptor antagonists than ZM241385. The affinity of LUF5451 for the A_2A receptor (K_i value = 13 nM) showed that the selectivity for this receptor subtype was lost and that a modest A_2B receptor selectivity was achieved. The 5‐(2‐phenylhydrazino) derivative LUF5475 showed a high A_2B receptor affinity (K_i = 7.6 nM), while it was equally active at A_2A receptors, being A_2B receptor‐selective with respect to A₁ and A₃ receptors. Drug Dev. Res. 48:95–103, 1999. © 1999 Wiley‐Liss, Inc.     

Pharmacological characterization of YM087, a potent, nonpeptide human vasopressin V1A and V2 receptor antagonist

The effects of YM087 (4’-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride), a novel nonpeptide vasopressin (AVP) receptor antagonist, on [³H]AVP binding to human AVP receptors (V_1A, V_1B and V₂) cloned and transiently expressed in COS-1 cells generated from monkey renal tissue were studied. Scatchard analysis of saturation isotherms for the specific binding of [³H]AVP to membranes, prepared from COS-1 cells transfected with human V_1A, V_1B and V₂ receptors, yielded an apparent equilibrium dissociation constant (K _d) of 0.67nM, 0.28nM and 2.14nM and a maximum receptor density (B _max) of 2180fmol/mg protein, 369fmol/mg protein and 2660fmol/mg protein, respectively. YM087 showed high affinity for AVP V_1A and V₂ receptors with K _i values of 6.3 and 1.1nM, respectively, but had no effect on [³H]AVP binding to AVP V_1B receptors. In COS-1 cells expressing either AVP V_1A or V_1B receptors, AVP caused a concentration-dependent increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i). YM087 inhibited the AVP-induced increase in [Ca²⁺]_i in COS-1 cells expressing AVP V_1A receptors in a concentration-dependent manner with an IC₅₀ value of 14.3nM, but did not influence this increase in AVP V_1B-receptor expressing cells. In contrast, stimulation of COS-1 cells expressing AVP V₂ receptors resulted in an accumulation of cAMP. YM087 inhibited AVP-induced cAMP production in COS-1 cells expressing AVP V₂ receptors in a concentration-dependent manner with an IC₅₀ value of 1.95nM. In all assays used, YM087 was devoid of any agonistic activity. These results suggest that YM087 is a potent nonpeptide dual human AVP V_1A and V₂ receptor antagonist, and that YM087 will be a powerful tool in investigation of the physiological and pathophysiological roles of AVP. Received: 15 July 1997 / Accepted: 23 September 1997     

奥美沙坦:一种新的血管紧张肽Ⅱ受体拮抗剂

奥美沙坦 (olmesartan)是最新的血管紧张肽Ⅱ受体 (AT1)拮抗剂 ,对不同程度的高血压均有很好的降压作用 ,病人对其亦有很好的耐受性。本文对该药的药效学、药动学和临床应用等研究作一综述     

Progress towards glucagon receptor antagonist therapy for Type 2 diabetes

Peptidal glucagon receptor antagonists and antiglucagon monoclonal antibodies lower glucose levels in diabetic rodent models, suggesting a potential to treat hyperglycaemia in Type 2 diabetics through the inhibition of glucagon function. Several research groups have discovered small molecule glucagon antagonists from multiple chemical series and at least one has been clinically evaluated. Although multiple compounds have blocked the rise in blood glucose levels in response to a glucagon challenge, no preclinical or clinical efficacy data from chronic studies have been reported. In general, drug candidate potency, pharmacokinetics, physical properties and cross-species potency have hindered progress and preclinical efficacy assessment. Recently, antisense oligonucleotides against the glucagon receptor have been described, providing a guiding post for the type of activity a small molecule glucagon antagonist may possess, as well as offering a potential therapeutic strategy.     

Involvement of cannabinoid CB(2) receptor-mediated response and efficacy of cannabinoid CB(2) receptor inverse agonist, JTE-907, in cutaneous inflammation in mice

Involvement of cannabinoid CB₂ receptor and effect of cannabinoid CB₂ receptor antagonist/inverse agonists on cutaneous inflammation were investigated. Mice ears topically exposed to an ether-linked analogue of 2-arachidonoylglycerol (2-AG-E) or selective cannabinoid CB₂ receptor agonist, {4-[4-(1,1-dimethylheptyl)-2,6-dimethoxy-phenyl]-6.6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl}-methanol (HU-308), had early and late ear swelling (0–24 h and 1–8 days after exposure, respectively). Both types of responses induced by 2-AG-E were significantly suppressed by oral administration of cannabinoid CB₂ receptor antagonist/inverse agonists, [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide}} (SR144528). In contrast, JTE-907 did not affect arachidonic acid-induced swelling. Orally administered JTE-907 (0.1–10 mg/kg) and SR144528 (1 mg/kg) also produced significant inhibition of dinitrofluorobenzene-induced ear swelling, with increased cannabinoid CB₂ receptor mRNA expression observed in the inflamed ear. These results suggest that cannabinoid CB₂ receptor is partially involved in local inflammatory responses and cannabinoid CB₂ receptor antagonist/inverse agonist has beneficial effects on ear swelling.     

Novel selective cannabinoid CB(1) receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

Aim:

To characterize the biological profiles of MJ08, a novel selective CB₁ receptor antagonist.

Methods:

Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB₁ and CB₂ receptor redistribution and intracellular Ca²⁺ ([Ca²⁺]_i) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice.

Results:

In radioligand binding assay, MJ08 selectively antagonized CB₁ receptor (IC₅₀=99.9 nmol/L). In EGFP-CB₁_U2OS cells, its IC₅₀ value against CB₁ receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 μmol/L) increased [Ca²⁺]_i in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB₁ cells. MJ08 (10 nmol/L–10 μmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA₂=10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB₁ cells with an EC₅₀ value of 78.6 nmol/L, which was lower than the EC₅₀ value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB₁ receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo.

Conclusion:

MJ08 is a novel, potent and selective CB₁ receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB₁ receptors.     

Intermolecular cross-talk between the prostaglandin E2 receptor (EP)3 subtype and thromboxane A2 receptor signalling in human erythroleukaemic cells

Background and purpose:

In previous studies investigating cross-talk of signalling between prostaglandin (PG)E₂ receptor (EP) and the TPα and TPβ isoforms of the human thromboxane (TX)A₂ receptor (TP), 17-phenyl trinor PGE₂-induced desensitization of TP receptor signalling through activation of the AH6809 and SC19220-sensitive EP₁ subtype of the EP receptor family, in a cell-specific manner. Here, we sought to further investigate that cross-talk in human erythroleukaemic (HEL) 92.1.7 cells.

Experimental approach:

Specificity of 17-phenyl trinor PGE₂ signalling and its possible cross-talk with signalling by TPα/TPβ receptors endogenously expressed in HEL cells was examined through assessment of agonist-induced inositol 1,4,5-trisphosphate (IP)₃ generation and intracellular calcium ([Ca²⁺]_i) mobilization.

Key results:

While 17-Phenyl trinor PGE₂ led to activation of phospholipase (PL)Cβ to yield increases in IP₃ generation and [Ca²⁺]_i, it did not desensitize but rather augmented that signalling in response to subsequent stimulation with the TXA₂ mimetic U46619. Furthermore, the augmentation was reciprocal. Signalling by 17-phenyl trinor PGE₂ was found to occur through AH6809- and SC19920-insensitive, Pertussis toxin-sensitive, G_i/G_βγ-dependent activation of PLCβ. Further pharmacological investigation using selective EP receptor subtype agonists and antagonists confirmed that 17-phenyl trinor PGE₂-mediated signalling and reciprocal cross-talk with the TP receptors occurred through the EP₃, rather than the EP₁, EP₂ or EP₄ receptor subtype in HEL cells.

Conclusions and Implications:

The EP₁ and EP₃ subtypes of the EP receptor family mediated intermolecular cross-talk to differentially regulate TP receptor-mediated signalling whereby activation of EP₁ receptors impaired or desensitized, while that of EP₃ receptors augmented signalling through TPα/TPβ receptors, in a cell type-specific manner.     

细胞外钙受体的结构特点以及临床应用的新领域

细胞外钙受体 (CaR)对调节机体细胞外钙 (Ca2 + o )平衡发挥着重要作用。CaR属于由G蛋白介导的受体 ,是由 10 79个氨基酸组成的多肽。CaR广泛分布于甲状旁腺、甲状腺C细胞、肾脏、肠、骨等参与钙调节的重要器官 ,其基因缺损可导致钙调节紊乱。由于CaR的生理意义非常重要 ,它已成为治疗钙代谢紊乱性疾病的靶点。CaR拮抗剂和激动剂可分别用于治疗甲状旁腺机能亢进、骨质疏松症和肾结石 ,颇具临床应用潜力     

Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (CysLT2) receptor

Background and purpose:

Cysteinyl leukotrienes (CysLTs) have been implicated in the pathophysiology of inflammatory and cardiovascular disorders. Their actions are mediated by CysLT₁ and CysLT₂ receptors. Here we report the discovery of 3-({[(1S,3S)-3-carboxycyclohexyl]amino}carbonyl)-4-(3-{4-[4-(cyclo-hexyloxy)butoxy]phenyl}propoxy) benzoic acid (HAMI3379), the first potent and selective CysLT₂ receptor antagonist.

Experimental approach:

Pharmacological characterization of HAMI3379 was performed using stably transfected CysLT₁ and CysLT₂ receptor cell lines, and isolated, Langendorff-perfused, guinea pig hearts.

Key results:

In a CysLT₂ receptor reporter cell line, HAMI3379 antagonized leukotriene D₄- (LTD₄-) and leukotriene C₄- (LTC₄-) induced intracellular calcium mobilization with IC₅₀ values of 3.8 nM and 4.4 nM respectively. In contrast, HAMI3379 exhibited very low potency on a recombinant CysLT₁ receptor cell line (IC₅₀ > 10 000 nM). In addition, HAMI3379 did not exhibit any agonistic activity on both CysLT receptor cell lines. In binding studies using membranes from the CysLT₂ and CysLT₁ receptor cell lines, HAMI3379 inhibited [³H]-LTD₄ binding with IC₅₀ values of 38 nM and >10 000 nM respectively. In isolated Langendorff-perfused guinea pig hearts HAMI3379 concentration-dependently inhibited and reversed the LTC₄-induced perfusion pressure increase and contractility decrease. The selective CysLT₁ receptor antagonist zafirlukast was found to be inactive in this experimental setting.

Conclusions and implications:

HAMI3379 was identified as a potent and selective CysLT₂ receptor antagonist, which was devoid of CysLT receptor agonism. Using this compound, we showed that the cardiac effects of CysLTs are predominantly mediated by the CysLT₂ receptor.     

内皮素受体拮抗剂CPU0213对异丙肾上腺素心肌病SERCA2a表达的改善作用

目的：研究异丙肾上腺素心肌病模型心肌细胞肌浆网钙ATP酶（sarco-endoplasmic reticulum ATPase 2a,SERCA2a）表达的改变,以及新型内皮素受体拮抗剂CPU0213的治疗作用。方法：雄性SD大鼠皮下给予异丙肾上腺素（2mg·kg^-1·d^-1）10d,治疗组动物在第6到第10天皮下给予CPU0213（30mg·kg^-1·d^-1）。各组动物颈动脉插管记录心功能指标：左心室收缩压（LVSP）,左心室舒张末期压（LVEDP）,和左心室压力变化最大速率（±dp/dtmax）。左心室心肌组织SERCA2a的mRNA及蛋白表达分别用逆转录聚合酶链反应（RT-PCR）和蛋白免疫印迹法（Western blotting）测定。结果：异丙肾上腺素引起左心室收缩和舒张功能明显下降,同时SERCA2a的mRNA及蛋白表达均显著下调（P〈0.05）。CPU0213显著提高SERCA2a表达（P〈0.05）,明显改善心功能（P〈0.05）。结论：CPU0213可通过逆转肌浆网钙调控蛋白SERCA2a的表达下调,使异丙肾上腺素引起的心功能下降得以恢复。本实验证明SERCA2a是β受体过度激活引发心衰过程中的重要靶点。内皮素受体介导了β受体过度激活状态下SER-CA2a的表达下调,是内皮素受体拮抗剂治疗心衰的重要依据之一。     

Synthetic approaches to site selective deuterium incorporation in a novel CRTh2 receptor antagonist clinical candidate

Selection of acidic or basic reaction conditions, combined with appropriate temperatures, allowed for site selective direct incorporation of deuterium at multiple positions in the 7‐azaindole‐3‐acetic acid CRTh2 receptor antagonist clinical candidate NVP‐QAV680. Copyright © 2014 John Wiley & Sons, Ltd.