1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成及抗真菌活性

报道了29个新的1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成与体外抗菌试验。结果表明,大多数化合物对大部分真菌有抑菌活性,化合物T₁,T₄,T₆,T₁₁,T₁₂,B₁,B₃,B₄和B₆对部分真菌抑菌活性优于或相当于奥昔康唑。     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED₅₀值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

4-((4-((2-取代苯氧基)乙基)-1-哌嗪)-甲基)-1,2-二氢喹啉-2-酮类化合物的合成及体外α-受体拮抗活性

目的研究DDPH类似物1,2-二氢喹啉-2-酮类化合物的合成及其体外α-受体拮抗活性。方法通过酰化、溴代、环合和取代反应等合成目的物;推测了异常中间体3-溴-4-溴甲基-1,2-二氢喹啉-2-酮(5)和3-溴-4-甲基-1,2-二氢喹啉-2-酮(6)的生成机理;测定目的物的体外α-受体拮抗活性。 结果设计、合成了12个新化合物II_1～6和IV_1～6,其中6个目的物1,2-二氢喹啉-2-酮类(IV_1～6)的结构经IR,¹HNMR,MS和HRMS确证;IV₃,IV₄和IV₆对兔主动脉环抑制作用较明显。结论化合物IV₃,IV₄和IV₆显示了一定的抑制活性,值得进一步研究。     

5-取代苯基,1-氢及1-正丙基吡唑烷酮-3化合物抗惊作用QASR的研究

研究了5-取代苯基吡唑烷酮-3衍生物中苯基取代基的变化对抗惊活性的影响。按照Topliss改进法设计并合成了。1-氢及1-正丙基取代的化合物各六个,找到了活性较强的化合物,为5-(对氟苯基)-1-丙基吡唑烷酮-3,其ED₅₀为14.7mg/kg。经QSAR研究,发现疏水参数∑π对活性影响较大,苯上取代基的立体参数B₄和电性参数Ⅰ×10²可以改进相关系数r。方程说明5-位苯上引入体积小的吸电子基团可使抗惊活性提高。     

N-(1-乙氧羰基-3-苯氨甲酰基丙基)甘氨酰甘氨酸衍生物的合成

报道4个N-(1-[1-乙氧羰基-3-(对甲)苯氨甲酰基]丙基甘氨酰｝-N-取代甘氨酸(XI_1～4)和5个1-[1-乙(或甲)氧羰基-3-(对甲)苯氨甲酰基]丙基-4-取代-1,4-哌嗪-2,5-二酮(XII_1～5)共9个估计有血管紧张素转化酶抑制活性化合物的合成和鉴定。所有这些化合物及9个相应的酯(X_1～9)均未见文献报道。药理初试结果,化合物XII₂,XII₅,XI₄和XII₁均有较强降压活性。     

(E)-1-芳基-2-咪唑乙酮和(E)-1-芳基-2-苯并咪唑乙酮取代苯腙衍生物的合成及其抗真菌活性

根据抗真菌药物的作用机理和构效关系,本文设计合成了61个(E)-1-芳基-2-咪唑乙酮和(E)-1-芳基-2-苯并咪唑乙酮取代苯腙衍生物,其中57个化合物是未知的。初步抑菌试验结果表明,大多数化合物对深部致病真菌具有不同程度的抑菌作用。当苯环上有2,6-Cl₂,2,4-Cl₂,p-Cl,p-NO₂,p-OCH₃,p-SCH₃取代时,抗真菌活性较强,特别是有p-OCH₃取代的化合物(如:13,29,45)抗真菌活性优于或相似于克霉唑,抗菌谱也较广。     

4-甲基-香豆素及4-甲基喹啉-2(1H)-酮的7位羟基、巯基与炔丙基卤代物的不同反应性

目的合成具有抗HIV活性的三环杂环化合物的关键中间体.方法 7-羟基-4-甲基-香豆素、7-羟基-4-甲基喹啉-2(1H)-酮、7-巯基-4-甲基-香豆素分别与3-氯-3-甲基-1-丁炔、3-溴丙炔反应得到相应产物,其结构经波谱确证.结果 4-甲基-香豆素的7位羟基发生正常的双分子亲核取代反应(SN2),得到炔丙基醚产物4、7和10,进一步热环合得到三环杂环化合物5、8和11;7-巯基-4-甲基-香豆素、7-巯基-4-甲基喹啉-2(1H)-酮与3-氯-3-甲基-1-丁炔反应分别得丙二烯醚双分子亲核取代反应(SN2′)产物聚集双键硫醚化合物12和14,且不能进一步热环合成三环杂环.结论 4-甲基-香豆素及4-甲基喹啉-2(1H)-酮的7位羟基、巯基与炔丙基卤代物表现出不同的反应性.     

6-(4′-取代酰胺基苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集作用

目的：6-(4′-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及抗血小板聚集活性的研究。方法：通过付-克反应、碳链延长、水解和环合反应得到两个关键中间体,然后通过酰化反应制得各种酰胺化合物;参考Born比浊法测定目标化合物的抗血小板聚集活性。结果：设计合成了24个6-(4′-取代酰胺基苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物,22个为首次报道;所有化合物在体外对ADP诱导的兔血小板聚集均有不同程度的抑制作用,第II类化合物的抑制作用强于第I类化合物,其中I₁,I₃,II₁,II₃,II₄,II₆和II₉的抑制作用均强于对照药CI-930,其中II₁和II₃的抑制作用最强,其IC₅₀约为CI-930的1/10。结论：其中一些化合物显示较强的抗血小板聚集活性,值得进一步研究。     

6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集的作用

为了寻找较理想的抗血栓药物,本文设计合成了6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物16个。对ADP诱导的大鼠体外血小板聚集,均有不同程度的抑制作用。其中,化合物Ⅱ₂,Ⅱ3和Ⅱ₄的作用大于CCI-17810,又以Ⅱ₄的作用为最强。     

3-甲基芬太尼衍生物QSAR研究

Hansch途径研究了一系列3-甲基芬太尼衍生物理化性质与镇痛活性间的关系。初步结果表明,镇痛活性与化合物的油/水分配系数之间无规律性变化;与R₂取代基的立体效应(如L,B₁～B₄及MR_R2)和疏水常数(π_R2)间有一定的匹配关系,与R₃取代基的Hammen常数(σ)呈抛物线型。引入1-β羟基亦颇为有利。从作用机理推测,该类衍生物的R₂和可能是与受体相结合的基团,R₁可能仅起药物转运的载体作用,1-β羟基也可能通过氢键参与与受体的互补部位缔合。     

Comparative pharmacology of human adenosine receptor subtypes – characterization of stably transfected receptors in CHO cells

Four adenosine receptor subtypes of the family of G protein-coupled receptors, designated A₁, A_2A, A_2B and A₃ are currently known. In this study all human subtypes were stably transfected into Chinese hamster ovary (CHO) cells in order to be able to study their pharmacological profile in an identical cellular background utilizing radioligand binding studies (A₁, A_2A, A₃) or adenylyl cyclase activity assays (A_2B). The A₁ subtype showed the typical pharmacological profile with 2-chloro-N⁶-cyclopentyladenosine (CCPA) as the agonist with the highest affinity and a marked stereoselectivity for the N⁶-phenylisopropyladenosine (PIA) diastereomers. In competition with antagonist radioligand biphasic curves were observed for agonists. In the presence of GTP all receptors were converted to a single low affinity state indicating functional coupling to endogenous G proteins. For A_2A adenosine receptors CGS 21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine) and N-ethylcarboxamidoadenosine (NECA) were found to be the most potent agonists followed by R- and S-PIA with minor stereoselectivity. The relative potencies of agonists for the A_2B adenosine receptor could only be tested by measurement of receptor-stimulated adenylyl cyclase activity. NECA was the most potent agonist with an EC₅₀-value of 2.3 μM whereas all other compounds tested were active at concentrations in the high micromolar range. Inhibition of NECA-stimulated adenylyl cyclase identified xanthine amino congener (XAC; 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]phenyl]-1,3-dipropylxanthine) as the most potent antagonist at this receptor subtype. The A₃ receptor was characterized utilizing the nonselective agonist [³H]NECA. The N⁶-benzyl substituted derivatives of adenosine-5′-N-methyluronamide (MECA) turned out to be the most potent agonists. The notion of xanthine-insensitivity of the A₃ receptor should be dropped at least for the human receptor as xanthines with submicromolar affinity were found. Overall, the pharmacological characteristics of the human receptors are similar to other species with some species-specific characteristics. In this study we present for the first time the comparative pharmacology of all known human adenosine receptor subtypes. The CHO cells with stably transfected adenosine receptors provide an identical cellular background for such a pharmacological characterization. These cells are valuable systems for further characterization of specific receptor subtypes and for the development of new ligands. Received: 14 July 1997 / Accepted: 26 September 1997     

Synthesis,pharmacological and biological screening of some novel pyrimidine derivatives

In the present study a new series of 4-substituted phenyl-6-(pyridin-2-yl)pyrimidin-2-ol (1–9) and 4-substituted phenyl-6-(pyridin-2-yl)pyrimidin-2-thiol (10–18) have been synthesized by cyclizing 3-substituted phenyl-1-(pyridin-2-yl)prop-2-en-1-one with urea/thiourea in the presence of NaOH as base (1a–18a). 3-Substituted phenyl-1-(pyridin-2-yl)prop-2-en-1-one was prepared by condensing 2-acetylpyridine with substituted benzaldehyde in the presence of 20 % NaOH as base. The structures of the newly synthesized compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectroscopic studies. Newly synthesized compounds were screened for their anti-inflammatory, analgesic, cytotoxic, and antitubercular activities studies. Few of the compounds exhibited excellent anti-inflammatory activities compared to standard drug diclofenac sodium. Some compounds have shown moderate analgesic activities compared to standard drug pentazocine. Also, some compounds have exhibited moderate cytotoxic and antitubercular activities.     

17β-Nitro-5α-androstan-3α-ol and its 3β-methyl derivative: Neurosteroid analogs with potent anticonvulsant and anxiolytic activities

Many 17-substituted androstan-3α-ol analogs act as positive allosteric modulators of GABA_A receptors and exert anticonvulsant and anxiolytic-like activity actions in animal models. The endogenous neurosteroid allopregnanolone (17β-acetyl; 1) is among the most potent of these. Here we demonstrate that 3α-hydroxy-17β-nitro-5α-androstane (2b) and its 3β-methyl analog (3α-hydroxy-3β-methyl-17β-nitro-5α-androstane; 2c) modulate GABA_A receptors as assessed by [³⁵S]t-butylbicyclo-phosphorothionate and [³H]flunitrazepam binding with potencies equivalent to or greater than 1. These compounds also had potencies equivalent to or greater than 1 in the pentylenetetrazol and 6 Hz seizure models in the mouse. Furthermore, 2b exhibited anxiolytic-like activity in the elevated zero maze. The 3β-hydroxy, 3α-desmethyl analog (2a) was devoid of activity on GABA_A receptors in vitro but had moderate activity in the seizure models, possibly as a result of epimerization in vivo at the 3-position. This conclusion was supported by the lack of in vivo activity of the 3β-hydroxy, 3α-methyl analog (2d), which is not expected to undergo epimerization. We conclude that nitro can serve as a bioisostere for acetyl at the 17β-position of 5α-androstan-3α-ol, such that the nitro analog fully retains the bioactivity of the endogenous neurosteroid at GABA_A receptors.     

云南甘草中新三萜成分的研究

自云南甘草(Clycyrrhiza yunnanensis)根中分离出10个化合物,经化学方法和光谱解析,鉴定9个为五环三萜类化合物:3β,21α,24-三羟基-齐墩果-12-烯-29-羧酸(Ⅰ)、3β,21α-二羟基-齐墩果-12-烯(Ⅱ)、3β,21α,24-三羟基-齐墩果-12-烯(Ⅲ)、桦木酸(Ⅳ)、23-羟基桦木酸(Ⅴ)、齐墩果酸(Ⅵ)、3β-羟基-16-氧-11,13(18)-二烯-3O-羧酸(Ⅶ)、24-羟基甘草内酯(Ⅷ)和21α-乙酰氧基木栓烷-3-酮(Ⅸ);另一个为β-胡萝卜甙(Ⅹ)。其中Ⅰ和Ⅱ为新化合物,分别命名为云南甘草皂甙元B1和B2。其余7个是已知物,但Ⅴ和Ⅸ首次得自甘草属植物,Ⅳ,Ⅵ和Ⅷ首次自云南甘草中分离得到。     

Further pharmacological characterization of the adenosine receptor subtype mediating inhibition of oxidative burst in human isolated neutrophils

The aims of this study were to characterize the adenosine receptor subtype mediating inhibition of superoxide anion generation induced by N-formyl-methionyl-leucylphenylalanine (fMLP) in human neutrophils and to test the hypothesis that adenosine 3′:5′-cyclic monophosphate (cAMP) is the second messenger mediating such inhibition. Superoxide anion generation induced by a submaximal concentration of fMLP (1 μM) was inhibited in a concentration-dependent manner by adenosine receptor agonists with a rank order of potency ofN-ethylcarboxamidoadenosine (NECA) > 2(4-[(2- carboxyethyl)phenyl]ethylamino)-5′-N-ethylcarboxamido adenosine (CGS 21680) > (R)-N⁶-phenyl-2-propyladenosine ((R)-PIA) > 2-Chloro-N⁶-(3-iodobenzyl)9-[5-methylcarbamoyl)-β-D-ribofuranosyl] adenine (2-Cl-IB-MECA) > N⁶-cyclopentyladenosine (CPA) > (S)-N⁶-phenyl-2-propyladenosine ((S)-PIA) ≥ N⁶-(4-amino-3-iodobenzyl) adenosine-5′-N-methyl-uronamide (AB-MECA); this order of potency is consistent with the activation of A_2A adenosine receptors. The nonselective A₁, A_2A, and A_2B receptor antagonist 8-p-(sulphophenyl) theophylline (8-SPT; 10 μM) produced blockade of each of the agonists (pK_B values 4.79–5.68). The selective A₁ adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM) and the selective A₃ adenosine receptor antagonist 3-(3-iodo-4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propylxanthine (I-ABOPX; 200 nM) also produced blockade of all the agonists (PK_B values 7.37–7.61 and 6.75–7.52, respectively); however, the concentrations required were higher than those which are considered selective for the A₁ or A₃ receptors. The selective A_2A receptor antagonist, 4-(2-[7-amino-2-(2-furyl) [1,2,4] triazolo [2,3-a] [1,3,5] triazin-5-yl amino]ethyl) phenol (ZM 241385; 100 nM), powerfully suppressed the inhibition of the oxidative burst induced by each of the agonists. A Schild analysis of the effects of ZM 241385, 1–100 nM, against NECA and CGS 21680 was carried out. ZM 241385 produced concentration-dependent, parallel shifts of the concentration–effect curves to both NECA and CGS 21680, with pA₂ values of 9.62 and 9.59, respectively. Together, these data establish that inhibition of the oxidative burst in human isolated neutrophils, induced by adenosine receptor agonists, is mediated by the A_2A receptor. NECA (0.01–10 μM) induced a concentration-dependent increase in the intracellular cAMP content of neutrophils. This effect was inhibited in a dose-dependent manner by ZM 241385 (0.001–10 μM), consistent with activation of A_2A adenosine receptors. The results clearly demonstrate that in human neutrophils inhibition of the fMLP—induced oxidative burst by adenosine receptor agonists is mediated via activation of A_2A adenosine receptors linked positively to cAMP. No evidence of A₁, A_2B, or A₃ adenosine receptor-mediated modulation of oxidative burst was found. Drug Dev. Res. 43:214–224, 1998. © 1998 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     

Microwave assisted synthesis of novel pyrazolone derivatives attached to a pyrimidine moiety and evaluation of their anti-inflammatory, analgesic and antipyretic activities

In the present research work, the motto was to develop new chemical entities as potential anti-inflammatory, analgesic and antipyretic agents. Various 4-(2-amino-6-(substituted)pyrimidin-4-yl)-3-methyl-1-(substituted)-1H-pyrazol-5(4H)-one derivatives (5a–5j) and their Schiff bases (6a–6j) were synthesized. The newly synthesized compounds were characterized by TLC and spectral data. The compounds containing pyrazolone and amino pyrimidine as basic moieties (5a–5j), were screened for their anti-inflammatory, analgesic and antipyretic activities, compounds 5a, 5c–5f, 5h exhibited activities nearly similar to the standard. The pharmacological studies reveal that the presence of 4-hydroxy, 4-methoxy, 4-(N,N-dimethylamino) or 2-hydroxy groups on phenyl ring at C₆ of amino pyrimidine exhibits anti-inflammatory, analgesic and antipyretic activities nearly similar to the standard and substitutions like 4-chloro, 2-nitro, 3-nitro or 4-nitro on same phenyl ring lead to a decrease in activities.     

Characterization of the cloned guinea pig leukotriene B4 receptor: comparison to its human orthologue

A cDNA clone coding for the guinea pig leukotriene B₄ (BLT) receptor has been isolated from a lung cDNA library. The guinea pig BLT receptor has an open reading frame corresponding to 348 amino acids and shares 73% and 70% identity with human and mouse BLT receptors, respectively. Scatchard analysis of membranes prepared from guinea pig and human BLT receptor-transfected human embryonic kidney (HEK) 293 EBNA (Epstein–Bar Virus Nuclear Antigen) cells showed that both receptors displayed high affinity for leukotriene B₄ (K_d value of 0.4 nM) and were expressed at high levels (B_max values ranging from 9 to 12 pmol/mg protein). The rank order of potency for leukotrienes and related analogs in competition for [³H]leukotriene B₄ specific binding at the recombinant guinea pig BLT receptor is leukotriene B₄>20-OH-leukotriene B₄>12(R)-HETE ((5Z,8Z,10E,12(R)14Z)-12-hydroxyeicosatetraen-1-oic acid)>12(S)-HETE ((5Z,8Z,10E,12(S)14Z)-12-Hydroxyeicosatetraen-1-oic acid)>20-COOH-leukotriene B₄>U75302 (6-(6-(3-hydroxy-1E,5Z-undecadienyl)-2-pyridinyl)-1,5-hexanediol)leukotriene C₄=leukotriene D₄=leukotriene E₄. For the human receptor the rank order of 12(S)-HETE, 20-COOH-leukotriene B₄ and U75302 was reversed. Xenopus melanophore and HEK aequorin-based reporter gene assays were used to demonstrate that the guinea pig and human BLT receptors can couple to both the cAMP inhibitory and intracellular Ca²⁺ mobilization signaling pathways. However, in the case of the aequorin-expressing HEK cells (designated AEQ17-293) transfected with either the guinea pig or human BLT receptor, expression of G_α16 was required to achieve a robust Ca²⁺ driven response. Leukotriene B₄ was a potent agonist in functional assays of both the guinea pig and human BLT receptors. U-75302 a leukotriene B₄ analogue which possesses both agonistic and antagonistic properties behaved as a full agonist of the guinea pig and human BLT receptors in AEQ17-293 cells and not as an antagonist. The recombinant guinea pig BLT receptor will permit the comparison of the intrinsic potencies of leukotriene B₄ receptor antagonists used in guinea pig in vivo models of allergic and inflammatory disorders.     

粉防己碱,小檗胺等四氢异喹啉类生物碱对大鼠脑内M-胆碱受体的作用

用放射受体结合方法,研究了36种四氢异喹啉类生物碱及其半合成衍生物对大鼠脑内M-胆碱受体的结合特性。实验发现,粉防己碱对M-胆碱受体的亲和力最高,其K_i值为7.3×10^-8mol/L。小檗胺、四氢黄连碱和半合成原小檗碱衍生物B₁亦具有较高亲和力,K_i值分别为1.9×10^-7,6.8×10^-7和8.1×10^-7mol/L。四氢小檗碱半合成原小檗碱衍生物B₂,B₃,B₄,B₅,B₆和半合成小檗胺衍生物E₁及半合成蝙蝠葛碱衍生物D₁对M-胆碱受体的亲和力为中等强度,K_i值在1～2×10^-6mol/L之间。实验结果提示,某些四氢异喹啉类生物碱的药理作用可能与M-胆碱受体有关。     

SDZ 216–525, a selective and potent 5-HT1A receptor antagonist

The pharmacological properties of SDZ 216–525, methyl 4-{4-[4(1,1,3-trioxo-2H,1,2-benzoisothiazol-2-yl)butyl]-1-piperazinyl}1H-indole-2-carboxylate, a new selective and potent 5-HT_1A receptor antagonist, are described in vitro (and comparisons made with those of MDL 73005 and NAN 190, two putative for 5-HT_1A receptor antagonists) and in vivo. In radioligand binding studies, SDZ 216–525 showed high affinity and selectivity for 5-HT_1A sites (pK_D = 9.2) as compared to 5-HT_1B, 5-HT_1C, 5-HT_1D, 5-HT₂ and 5-HT₃ sites (pK_D= 6.0, 7.2, 7.5, 5.2 and 5.4, respectively). The affinity of the compound for α₁, α₂, β₂ and β₂ adrenoceptors. and dopamine D₂ receptors was at least 50–100 times lower than for 5-HT_1A sites. The effects of SDZ 216–525, MDL 73005 and NAN 190 on 5-HT₁ receptor-linked second messengers were characterized in the following tests: inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus (5-HT_1A), rat substantia nigra (5-HT_1B) and calf substantia nigra (5-HT_1D) and stimulation of inositol phosphate production in pig choroid plexus (5-HT_1C). SDZ 216–525 potently antagonised the effects of 8-OH-DPAT (8-hydroxy-2[N-diprophyl-amino]-tetralin) on 5-HT_1A receptors (pK_B = 10) and displayed no intrinsic activity in this test, whereas it behaved at best as a weak antagonist on the other receptor models pK_B values < 6.9). NAN 190 also behaved as a potent antagonist at 5-HT_1A receptors (pK_B = 8.7), whereas MDL 73005 displayed potent and nearly full agonism at 5-HT_1A receptors (pEC₅₀ = 7.3, E_max = 92%). Both compounds behaved broadly similarly to SDZ 216–525 in the other models. In vivo, SDZ 216–525 did not induce forepaw treading or flat body posture in lighlty44 reserpinies rats at up to 1 mg/kg s.c., whereas the behavioural responses to a submaximal dose of 8-OH-DPAT (0.25 mg/kg s.c.) were inhibited dose dependently by SDZ 216–525 over the range 0.03−1 mg/kg s.c. Similarly, SDZ 216–525 over the same dose range suppressed dose dependently the hypothermic effects of 8-OH-DPAT. These data demonstrate SDZ 216–525 to be a potent and selective 5-HT_1A receptor antagonist in vitro and in vivo.