异戊塞平和克塞平对大鼠脑内各受体亲和力的比较及慢性给药后的受体下调作用

用放射配体受体结合法测定表明:克塞平对多巴胺D_1受体的亲和力较异戊塞平高近20倍。两药对其它各受体的亲和力差別不大。慢性给药后,异戊塞平和克塞平均能使大鼠脑皮层5-HT_2受体的密度显著下降,而亲和力变化不明显。这种下调5-HT_2受体的作用发生在给异戊塞平后1～2周之间,给克塞平后的2～3周之间。慢性给药3周,异戊塞平和克塞平均未使大鼠脑皮层的β受体密度及亲和力产生显著变化。     

某些四氢异喹啉类生物碱对大鼠脑内多巴胺和5-羟色胺受体的作用

本文报道十二种四氢异喹啉类生物碱对大鼠脑内D-2,5-HT₁和5-HT₂受体的结合特性。其中l-千金藤碱(l-STP)对这三种受体均有较高的亲和力,其Ki值分别为1.7×10^-7,9.4×10^-8和1.8×10^-7mol。l-莲碱(l-REM)对5-HT₂受体的亲和力与Z-STP相似(Ki=1.7×10^-7mol)。THB,THC和THJ对D-2受体的亲和力介于l-SPD和l-THP之间。本文报道的多数生物碱能同时影响两种或两种以上受体部位的结合特性,提示它们对单胺神经系统可能有复杂的相互作用。     

美西律衍生物对α1肾上腺素受体的作用

为寻找新的α₁受体阻断剂,用[³H]-WB4101配体测定法测定了18种美西律衍生物。结果表明,其中6种化合物对大鼠脑皮层α₁受体有不同程度的亲和力。凡具有手性碳结构的化合物亲和力都较高。化合物M-85001的亲和力较妥拉唑林(tolazoline)高一个数量级并能抑制苯肾上腺素引起的大鼠肛尾肌收缩,其pA₂(6.86)与pK_i(6.51)相近。结果提示,美西律衍生物对α₁-受体的亲和力可能与手性碳结构有关,从美西律衍生物中研制新的α₁-受体阻断剂是有前途的。     

5-HT2受体介导大鼠DRG神经元膜GABA-激活电流的增强作用

目的探讨5-HT对大鼠DRG神经元膜GABA-激活电流的调节作用及其机制。方法在新鲜分离的大鼠DRG神经元标本上，以全细胞膜片钳技术记录膜电流，用排管快速换液装置行胞外给药，以胞内透析技术分析信号转导途径。结果给予GABA可使多数受检细胞产生浓度依赖性内向电流(I_GABA)。预加5-HT，可使I_GABA增加。此效应可被5-HT₂受体特异性激动剂α-methyl-5-HT(1×10^-6 mol·L^-1)所模拟，被5-HT₂受体选择性拮抗剂cyproheptadine所阻断。在部分细胞，5-HT本身可引起由5-HT₃受体介导的快速内向电流，但并未发现该电流与5-HT对I_GABA的增强作用有必然的联系。从GABA激活电流的量效曲线可见，预加5-HT后和对照曲线相比，阈浓度不变、EC₅₀值相近，I_GABA最大值增加33.6%。胞内透析GDP-β-S或H-7可取消5-HT增强I_GABA的效应，而透析H-9无效。结论5-HT可增强GABA-激活电流，其机制为5-HT₂受体激活后通过PKC引起GABA_A受体胞内磷酸化所致。     

脑5-HT1A/1B、α2受体及腺苷酸环化酶参与了胍丁胺的抗抑郁作用

为了在单胺受体及受体后腺苷酸环化酶(adenylate cyclase,AC)水平探讨胍丁胺(agmatine,AGM)抗抑郁作用的精细机制,采用小鼠悬尾实验和强迫游泳实验观察AGM抗抑郁行为改变。采用放射免疫方法测定大鼠前额皮层突触膜蛋白AC活性。结果表明,AGM(5～40 mg·kg^-1,ig)在小鼠悬尾实验和强迫游泳实验模型上均有显著抗抑郁活性。同时伍用β受体/5-HT_1A/1B受体阻断剂吲哚洛尔(pindolol, PIN, 20 mg·kg^-1, ip)、 α₂肾上腺素受体拮抗剂育亨宾(yohimbine, YOH, 5～10 mg·kg^-1, ip)或咪唑克生(idazoxan, IDA, 4 mg·kg^-1, ip)对AGM(40 mg·kg^-1, ig)的抗抑郁活性具有显著拮抗效应; 而β受体阻断剂普萘洛尔(propranolol, PRO, 5～20 mg·kg^-1, ip)或5-HT₃受体拮抗剂曲匹西隆(tropisetron, TRO, 5～40 mg·kg^-1, ip)对AGM(40 mg·kg^-1, ig)的抗抑郁活性无显著影响。AGM(0.1～6.4 μmol·L^-1)与大鼠前额皮层提取的突触膜共孵可剂量依赖地激活AC活性, 而PIN(1 μmol·L^-1)或YOH(0.25～1 μmol·L^-1)均显著拮抗AGM(6.4 μmol·L^-1)对AC的激活作用; 慢性给予大鼠AGM(10 mg·kg^-1, ig, bid)或氟西汀(fluoxetine, FLU, 10 mg·kg^-1, ig, bid) 2 w也显著增强大鼠前额皮层基础及Gpp(NH)p 预激活的AC活性。本研究表明, 调节脑内5-HT_1A/1B和α₂等受体功能, 并激活前额皮层AC可能是AGM抗抑郁活性的重要机制之一。     

新型5-HT2A选择性配体N-取代哌啶-4-苯硫醚和砜类衍生物的合成及其生物活性

目的为寻找新型的5-HT_2A受体选择性配体,设计合成了一系列二芳烷基哌啶类化合物的含硫衍生物。方法以2,3-二甲氧基硫酚为原料,经烃化、氧化和水解等反应合成3个N-取代哌啶-4-苯硫醚和砜类化合物,所有目标化合物结构均经元素分析、¹HNMR谱、质谱和红外光谱确证,并测定其对5-HT_2A,5-HT_2C,5-HT₆和5-HT₇受体及其他一些中枢神经递质受体的体外亲和力。结果3个目标化合物(2a-2c)及5个中间体均为新化合物。体外受体竞争结合试验结果表明2a-2c均有较高的5-HT_2A受体选择性。结论此类化合物对5-HT_2A受体的选择性较高,值得进一步研究。     

2010～2015年浙江省11家医院肺癌患者5-HT3受体拮抗药应用分析

摘 要 目的：了解2010～2015年浙江省11家医院肺癌患者5-HT₃受体拮抗药的应用情况和趋势,促进其合理用药。方法：抽取2010～2015年浙江省11家医院肺癌患者的医嘱用药数据,对其用药金额、用药频度（DDDs）、限定日费用（DDC）进行回顾性分析。结果：2010～2015年,浙江省11家医院肺癌患者使用5-HT₃受体拮抗药的用药金额逐年上升,但在总金额中的占比呈下降趋势,而2015年5-HT₃受体拮抗药不论用药金额还是占总用药金额比例都有所升高。6年内使用金额比例排名首位的分别为托烷司琼（2010～2014年）和帕洛诺司琼（2015年）。5-HT₃受体拮抗药DDDs排名首位是托烷司琼（2010～2015年）,DDC排名首位为帕洛诺司琼。结论：浙江省11家医院肺癌患者使用的5-HT₃受体拮抗药基本合理,安全有效、经济方便的5-HT₃受体拮抗药在临床使用中占优势。     

人参皂甙Rb1和Rg1对小鼠中枢神经递质受体和脑内蛋白质合成的影响

应用放射配基结合法测定了人参皂甙Rb₁和Rg₁对α₁,α₂,β肾上腺素能受体、M胆碱能受体、5-羟色胺、多巴胺及GABA等七种受体的作用。结果均不能证明它们对这七种受体有亲和力。但给动物ip药物连续5天,Rb₁和Rg₁均能使中枢M胆碱受体密度显著增高。Rb₁及Rg₁还能显著增加脑内蛋白质的含量。上述实验结果对解释人参的中枢作用提供了重要证据。     

双重作用的多巴胺D2/5-HT2A受体拮抗剂比较药效团分析

双重作用的多巴胺D₂/5-HT_2A受体拮抗剂是开发非典型抗精神病药物的有效途径,但最新研究显示, 非典型抗精神病药物将显著增加患者因心律失常及其他心脏疾病而猝死的风险,本文对D₂/5-HT_2A受体拮抗剂的药效团模型以及可能引起心血管风险的α_1A肾上腺素受体拮抗剂和hERG K⁺通道阻断剂的药效团模型进行比较分析,从药效团模型的角度分析多靶点药物的设计。     

心喘灵(XC-1)及其衍生物XC-2对肾上腺素受体及动脉平滑肌的作用

本文用放射配基结合法研究了心喘灵(XC-1)及其衍生物XC-2对肾上腺素受体的亲和力,用离体器官方法观察了二者对α受体功能的影响,用酶分析法研究了两药对β受体功能的影响。两药各种作用强度相近,对大鼠脑皮层细胞膜α受体有中等强度亲和力(Ki10^-6mol/L),对兔主动脉和大鼠肛尾肌α₁受体均有中等强度阻断作用,但对大鼠输精管突触前α₂受体只有微弱的阻断作用。二药抑制由ISO激动的腺苷酸环化酶活性的IC₅₀均为3.6×10^-5mol/L。此外,二者都能拮抗CaCl₂,KCl和5-HT引起的主动脉条收缩反应并有直接扩张血管的作用。     

Studies on the receptor profile of bisoprolol

The in vitro binding affinity of (+/-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2- propranol hemifumarate (bisoprolol, EMD 33 512) to beta 1-, beta 2-, alpha 1-, alpha 2-, D1-, D2-, 5-HT2- and muscarinic cholinergic receptors of rat was compared with that of atenolol, betaxolol and propranolol. Bisoprolol showed a high specific binding affinity to beta 1-adrenoceptors (heart) and a low specific binding affinity to beta 2-adrenoceptors (lung). The beta 1-selectivity of bisoprolol (beta 2/beta 1 = 34.7) proved to be higher than that of atenolol (8.7) and betaxolol (12.5). Propranolol (0.59) was non-selective as expected. Bisoprolol and atenolol exhibited no remarkable binding affinity to alpha 1-, alpha 2-, D1-, D2-, 5-HT2- and muscarinic cholinergic receptors at concentrations up to 1 X 10(-4) mol/l. For betaxolol binding affinities for alpha 2-, D2- and 5-HT2-receptors were found with IC50 values ranging between 2 X 10(-5) and 7 X 10(-5) mol/l. For propranolol binding affinities for alpha 1-, alpha 2-, D1-, D2- and 5-HT2-receptors were found with IC50 values ranging between 2 X 10(-6) and 9 X 10(-5) mol/l.     

Mechanisms of anabolic androgenic steroid modulation of alpha(1)beta(3)gamma(2L) GABA(A) receptors

Modulation of GABA(A) receptors induced by both anabolic androgenic steroids (AAS) and the benzodiazepine (BZ) site agonist, zolpidem, show equivalent dependence upon gamma subunit composition suggesting that both compounds may be acting at a shared allosteric site. Here we have characterized modulation induced by the AAS, 17alpha-methyltestosterone (17alpha-MeT), for responses elicited from alpha(1)beta(3)gamma(2L) GABA(A) receptors and compared it to modulation induced by the BZ site agonists, zolpidem and diazepam. For responses elicited by brief pulses of 20 microM GABA, both the AAS and the BZ site compounds significantly increased the peak current amplitudes and total charge transfer, although 17alpha-MeT was an appreciably weaker agonist than either diazepam or zolpidem at alpha(1)beta(3)gamma(2L) receptors. Neither class of modulator enhanced peak current amplitudes for responses elicited by mM concentrations of GABA. BZ site compounds altered time constants of deactivation, desensitization, and recovery from desensitization, however 17alpha-MeT had no overall effect on these parameters. Experiments in which 17alpha-MeT and BZ site ligands were applied concomitantly indicated that potentiation elicited by 17alpha-MeT and zolpidem were additive and that potentiation by 17alpha-MeT could be elicited in the presence of concentrations of flumazenil that blocked BZ potentiation. Finally, kinetic modeling suggests that while effects of 17alpha-MeT can be simulated by altering receptor affinity, the data for these alpha(1)beta(3)gamma(2L) receptors were best fitted by simulations in which 17alpha-MeT increases transitions into the singly liganded open state. Taken together, our results suggest that 17alpha-MeT does not act at the high-affinity BZ site, but may elicit some of its effects at the low affinity BZ site or at a novel site.     

Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology.

Atypical antipsychotic drugs have revolutionized the treatment of schizophrenia and related disorders. The current clinically approved atypical antipsychotic drugs are characterized by having relatively low affinities for D(2)-dopamine receptors and relatively high affinities for 5-HT(2A) serotonin receptors (5-HT, 5-hydroxytryptamine (serotonin)). Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug that is reported to be a high-affinity D(2)-dopamine receptor partial agonist. We now provide a comprehensive pharmacological profile of aripiprazole at a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal a number of interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole has highest affinity for h5-HT(2B)-, hD(2L)-, and hD(3)-dopamine receptors, but also has significant affinity (5-30 nM) for several other 5-HT receptors (5-HT(1A), 5-HT(2A), 5-HT(7)), as well as alpha(1A)-adrenergic and hH(1)-histamine receptors. Aripiprazole has less affinity (30-200 nM) for other G protein-coupled receptors, including the 5-HT(1D), 5-HT(2C), alpha(1B)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, and beta(2)-adrenergic, and H(3)-histamine receptors. Functionally, aripiprazole is an inverse agonist at 5-HT(2B) receptors and displays partial agonist actions at 5-HT(2A), 5-HT(2C), D(3), and D(4) receptors. Interestingly, we also discovered that the functional actions of aripiprazole at cloned human D(2)-dopamine receptors are cell-type selective, and that a range of actions (eg agonism, partial agonism, antagonism) at cloned D(2)-dopamine receptors are possible depending upon the cell type and function examined. This mixture of functional actions at D(2)-dopamine receptors is consistent with the hypothesis proposed by Lawler et al (1999) that aripiprazole has "functionally selective" actions. Taken together, our results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of "functionally selective" activation of D(2) (and possibly D(3))-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors--particularly 5-HT receptor subtypes (5-HT(1A), 5-HT(2A)).     

Affinity of cyamemazine metabolites for serotonin, histamine and dopamine receptor subtypes

Animal and human pharmacological studies indicate that the antipsychotic action of cyamemazine results from blockade of dopamine D(2) receptors, its anxiolytic properties from serotonin 5-HT(2C) receptor antagonism and the low incidence of extrapyramidal side effects from a potent 5-HT(2A) receptor antagonistic action. Cyamemazine is metabolized in monodesmethyl cyamemazine and cyamemazine sulfoxide, which are not known for their affinities for serotonin, dopamine and other brain receptor types considered to mediate central nervous systems effects of drugs. Hence, metabolite affinities were determined in human recombinant receptors expressed in CHO cells (hD(2) and hD4.4 receptors, h5-HT(1A), h5-HT(2A), h5-HT(2C) and h5-HT(7) receptors and hM(1), hM(2) and hM(3) receptors) and HEK-293 cells (h5-HT(3) receptors) or natively present in rat cerebral cortex (non-specific alpha(1)- and alpha(2)-adrenoceptors, GABA(A) and GABA(B) receptors) and guinea pig cerebellum (H(1) central histamine receptors) membranes. Monodesmethyl cyamemazine showed a neurotransmitter receptor profile similar to that of its parent compound cyamemazine, i.e.: high affinity for h5-HT(2A) receptors (K(i)=1.5 nM), h5-HT(2C) receptors (K(i)=12 nM) and hD(2) receptors (K(i)=12 nM). Cyamemazine sulfoxide showed high affinity for h5-HT(2A) receptors (K(i)=39 nM) and histamine H(1) receptors (K(i)=15 nM) and a reduced affinity for D(2) and 5-HT(2C) receptors. Therefore, monodesmethyl cyamemazine can contribute to enhance and prolong the therapeutic actions of cyamemazine. Further investigation is required to see if the high affinities of cyamemazine sulfoxide for H(1) and 5-HT(2A) receptors are of therapeutic benefit against sleep onset insomnia and/or sleep maintenance insomnia respectively.     

Comparison of the effects of zaleplon,zolpidem, and triazolam at various GABA(A) receptor subtypes

The pyrazolopyrimidine zaleplon is a hypnotic agent that acts at the benzodiazepine recognition site of GABA(A) receptors. Zaleplon, like the hypnotic agent zolpidem but unlike classical benzodiazepines, exhibits preferential affinity for type I benzodiazepine (BZ(1)/omega(1)) receptors in binding assays. The modulatory action of zaleplon at GABA(A) receptors has now been compared with those of zolpidem and the triazolobenzodiazepine triazolam. Zaleplon potentiated GABA-evoked Cl(-) currents in Xenopus oocytes expressing human GABA(A) receptor subunits with a potency that was higher at alpha1beta2gamma2 receptors than at alpha2- or alpha3-containing receptors. Zolpidem, but not triazolam, also exhibited selectivity for alpha1-containing receptors. However, the potency of zaleplon at these various receptors was one-third to one-half that of zolpidem. Zaleplon and zolpidem also differed in their actions at receptors containing the alpha5 or gamma3 subunit. Zaleplon, zolpidem, and triazolam exhibited similar patterns of efficacy among the different receptor subtypes. The affinities of zaleplon for [(3)H]flunitrazepam or t-[(35)S]butylbicyclophosphorothionate ([(35)S]TBPS) binding sites in rat brain membranes were lower than those of zolpidem or triazolam. Furthermore, zaleplon, unlike zolpidem, exhibited virtually no affinity for the peripheral type of benzodiazepine receptor.     

The novel anxiolytic ELB139 displays selectivity to recombinant GABA(A) receptors different from diazepam

A chemically heterogeneous group of compounds acts at the benzodiazepine (BZ) recognition site of the diverse gamma-aminobutyric acid type A (GABA(A)) receptor complexes which can assemble from more than 16 known subunits. Most 1,4-BZs like diazepam recognize all GABA(A)/BZ receptors containing the alpha1-3 or alpha5 together with any beta and the gamma2 subunit. Other compounds differentiate less, e.g. Ro15-4513, that additionally recognizes alpha4- and a6-containing receptors, or differentiate more, e.g. zolpidem, that recognizes preferentially alpha1-containing receptors. Here we describe the functional properties of 1-(4-chloro-phenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on (ELB139) in the presence and absence of the BZ receptor antagonist flumazenil (Ro15-1788) on recombinant alphaibeta2gamma2 (i=1-5) receptor subtypes expressed in HEK 293 cells. The properties were measured with the whole-cell variation of the patch-clamp technique and compared to those of diazepam. Like the latter, ELB139 did not potentiate GABA-induced currents in alpha4-containing receptors, but it displays functional subtype specificity between alpha1, alpha2, alpha3, and alpha5beta2gamma2 receptors with highest potency in alpha3-containing receptors but highest efficacy in alpha1- or alpha2-containing receptors, respectively. ELB139 acted as a partial agonist on these receptor subtypes reaching 40-50% of the efficacy of diazepam.     

Interaction of the beta adrenergic receptor antagonist bucindolol with serotonergic receptors

Bucindolol is a nonselective beta-adrenergic receptor antagonist that has additional vasodilating properties. Because some beta-adrenergic receptor antagonists such as cyanopindolol are used as 5-HT1A/5-HT1B receptor antagonists, we tested the hypothesis that bucindolol can interact with 5-HT receptors. Both in vitro and in vivo methods were used to examine the interaction of bucindolol with 5-HT receptors relevant to the cardiovascular system-the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors-and with alpha1-adrenergic receptors. In binding studies, bucindolol displayed high affinity for the 5-HT1A receptor (Ki, 11 nM), modest affinity for the 5-HT2A receptor (Ki, 382 nM), and no measurable affinity for the 5-HT1D receptor; binding affinity for the 5-HT2B receptor was not studied. Bucindolol also displayed significant binding affinity (Ki, 69 nM) for the alpha1-adrenergic receptors. Alpha1-Adrenergic receptor antagonist activity was confirmed by the ability of bucindolol (1 mg/kg) to act as a competitive antagonist against 0.01-30 microg/kg phenylephrine-induced pressor responses in conscious rats. In conscious permanently instrumented rats, bucindolol (0.1-3.0 mg/kg, i.v.) did not cause bradycardia similar to that elicited by the 5-HT1A-receptor agonist 8-OH-DPAT (3-300 microg/kg, i.v.), nor did bucindolol (1 mg/kg) block the 8-OH-DPAT-induced bradycardia. Bucindolol (10(-9)-10(-5) M) did not cause relaxation in the PGF2alpha-contracted, endothelium-intact porcine coronary artery, nor did bucindolol (10(-5) M) block 5-HT-induced coronary artery relaxation, indicating that bucindolol does not have significant interactions at the 5-HT1D receptor. Bucindolol also displayed no agonist activity at the 5-HT2A and 5-HT2B receptor (endothelium-denuded rat thoracic aorta and rat stomach fundus, respectively), but did act as a weak 5-HT2A-receptor antagonist (-log K(B) [M] = 5.4+/-0.1) and 5-HT2B-receptor antagonist (-log K(B) [M] = 7.8+/-0.1). Thus, these data suggest that bucindolol lacks the ability to activate the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptor, but can block alpha1-adrenergic receptors and act as a weak 5-HT2A- and 5-HT2B-receptor antagonist. The relevance of these serotoninergic effects as it pertains to the mechanism of bucindolol-induced vasodilation is unknown.     

Asenapine: a novel psychopharmacologic agent with a unique human receptor signature

Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder. We determined and compared the human receptor binding affinities and functional characteristics of asenapine and several antipsychotic drugs. Compounds were tested under comparable assay conditions using cloned human receptors. In comparison with the antipsychotics, asenapine showed high affinity and a different rank order of binding affinities (pKi) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8], 5-HT2C [10.5], 5-HT5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors (alpha1 [8.9], alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors (D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]). It had much lower affinity (pKi相似文献   

In vitro pharmacological profile of YM-43611, a novel D2-like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors.

1. We investigated some neurochemical properties of a novel benzamide, YM-43611, [(S)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-cyclopropylcarbonylamino+ ++-2- methoxybenzamide] in comparison with putative D2-like receptor antagonists using both rat and human cloned dopamine D2-like receptors in vitro. 2. Receptor binding studies revealed that YM-43611 had appropriately potent affinities for both rat and human D2-like receptors, with moderate selectivity for D3 receptors and high selectivity for D4 receptors over D2 receptors (Ki values (nM) for rat receptors: D2, 165; D3, 35.5; D4, 1.85, and for human receptors: D2, 42.9; D3, 11.2; D4, 2.10). 3. YM-43611 displayed weak or negligible affinity for other neurotransmitter receptors, namely D1, D5, alpha(1), alpha(2), beta, 5-HT1A, 5-HT2A, 5-HT3, H1, M1 and M2 receptors. 4. Dopamine stimulated low-Km GTPase activity on membranes from Chinese hamster ovary (CHO) cells expressing the human D2-like receptor subtype. This response to dopamine of low-Km GTPase activity was inhibited by use of putative D2-like receptor antagonists. YM-43611 showed a moderate selectivity for D3 receptors (Ki = 45.5 nM) and a high selectivity for D4 receptors (Ki = 3.28 nM) over D2 receptors (Ki = 70.6 nM). 5. Dopamine inhibited forskolin-stimulated adenylate cyclase in intact CHO cells expressing the human D2-like receptor subtype. YM-43611 shifted the inhibition curve of dopamine on respective D2-like receptor subtype-mediated cyclic AMP formation to the right in a parallel fashion, showing a pA2 value of 7.42 (38.1 nM) for D2 receptors, a pKB value of 8.06 (8.68 nM) for D3 receptors, and a pA2 value of 8.42 (3.77 nM) for D4 receptors. 6. YM-43611 but not the other D2-like receptor antagonists exhibited good selectivity with respect to dual antagonism for D3 and D4 receptors in both receptor binding and functional assays. 7. These results indicate that YM-43611 is a novel D2-like receptor antagonist with high potency and selectivity for both D3 and D4 receptors. YM-43611 is therefore expected to be valuable in exploration of the physiological role of D3 and D4 receptors.     

Binding profile of SM-9018, a novel antipsychotic candidate

The present study employed various receptor-binding assays to clarify the biochemical characteristics of SM-9018. SM-9018 possessed very high affinity for 5-HT2, D2 and 5-HT1A receptors (Ki = 0.61, 1.4 and 2.9 nM, respectively), and it had moderate affinity for alpha 1 and D1 receptors (Ki = 17 and 41 nM, respectively). However, SM-9018 had only negligible affinity for alpha 2, opiate, glutamate, phencyclidine, benzodiazepine and GABAA receptors. These results suggest that SM-9018 may be a novel antipsychotic agent with binding affinity for 5-HT2 and 5-HT1A receptors.