四氢异喹啉类生物碱对大鼠脑内α肾上腺素受体的作用

应用放射受体结合法研究了近30种四氢异喹啉类(TIQs)生物碱对大鼠脑内α肾上腺素受体的作用。其中l-CBN,l-THC和l-STP对α₁受体亲和力最高,K_i值为～2.0×10^-7mol/L。其次是DHS,XLP和l-DCT,K_i值分别为4.7×10^-7,6.5×10^-7和7.6×10^-7mol/L。DHS对α₂受体亲和力最高(K_i=1.25×10^-6mol/L),l-REM次之。对α受体亚型亲和力选择比K_i(alpha-2)/Ki(alpha-1)最高的是l-STP(357) 和XLP(154),它们对α₂受体几无亲和力(K_i>10^-4mnl/L)。提示l-STP和XLP对α₁受体有较高的选择性。l-SPD和l-THP对α₁和α₂受体亲和力相近,均为中等强度。THJ,DRC及l-TTD等6种TIQs对α₁和α₂受体均无亲和力(K_i>10^-4mnl/L)。     

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-HT_1和5-HT_2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~(-7)mol。l-莲碱(l-REM)对5-HT_2受体的亲和力与Z-STP相似(Ki=1.7×10~(-7)mol)。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。     

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。     

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。     

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。     

三七皂苷的口服吸收机制

目的研究三七总皂苷(PNS)的口服吸收机制。方法采用Caco-2细胞和动物等模型研究PNS中人参皂苷Rb_l(Rb_l)和人参皂苷Rg_l(Rg_l)的胃肠道内稳定性、肠道黏膜吸收机制及吸收过程中胃、肠及肝对药物的影响。结果Rb_l和Rg_l在胃液酸性环境下易被破坏，而在近中性环境内基本保持稳定。Rb_l和Rg_l在大肠内容物中易降解，尤以Rb_l降解较为明显；二者在小肠内容物中则相对稳定。Rb_l和Rg_l在Caco-2细胞层的摄取受温度的影响，而pH的变化及环孢菌素A的加入对二者摄取均无显著性影响。在实验考察的浓度范围内，细胞内Rb_l(或Rg_l)的摄取量随Rb_l(或Rg_l)的浓度的增加而呈线性增加，Rb_l(或Rg_l)单体与总皂苷中的Rb_l(或Rg_l)在Caco-2细胞模型中的吸收特性无明显差异。而Rg_l的细胞摄取量［(1.07±0.16) μg·mg^-1(protein)］(C₀=1 mg·mL^-1)相对Rb_l［(0.77±0.03) μg·mg^-1(protein)］(C₀=1 mg·mL^-1)较高。Caco-2细胞转运实验表明，Rb_l和Rg_l单体的转运透过系数(P_app)分别为(5.9±1.0)×10^{-8cm·s-1和(2.59±0.17)×10-7 cm·s-1(C₀=1 mg·mL-1)，二者转运都不受环孢菌素A影响。PNS溶液灌胃、十二指肠及门静脉给药后测得Rb_l大鼠绝对生物利用度分别为0.71%，2.75%和65.77%；Rg_l分别为3.29%，6.60%和50.56%。结论三七总皂苷(包括Rb_l和Rg_l)的肠道吸收机制为单纯被动扩散，吸收过程不受细胞膜内P-gp和MRP外排载体的调控，PNS中其他成分对Rb_l或Rg_l的吸收特性无明显影响。胃液的酸性环境、大肠菌丛产生的酶及肝脏的首过作用均对其口服吸收产生影响，而肠道黏膜的透过性低是其口服吸收差的主要影响因素。}     

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。     

山莨菪碱对乙酰胆碱和去甲肾上腺素引起的兔虹膜释放前列腺素的影响

本文研究了654-2对Ach及NE引起的兔虹膜释放PGE₂及6-keto-PGF_1α作用的影响。Ach及NE使虹膜释放PGs增加,654-2对Ach释放PGs的作用呈剂量依赖性抑制,当654-2浓度为3×10^-5mol/L时,Ach(5x10^-5mol/L)引起的PGE₂及6-keto-PGF_1α的释放量分别降低31%及30%。654-2浓度高于6x10^-5mol/L时显著抑制NE(5x10^-5mol/L)释放虹膜PGs的作用,当654-2浓度为3x10^-4mol/L时,使NE增加虹膜释放PGE:及6-keto-PGF_1α的量分别从62%及34%降至7.5%及4%(p<0.01)。654-2抑制PGs释放对其抗感染性休克等作用可能是有利的。     

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D₁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-HT₂受体的密度显著下降,而亲和力变化不明显。这种下调5-HT₂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。     

极谱法研究辅酶Q10与β-环糊精的包结行为

目的研究辅酶Q_{10与β-环糊精(β-CD)的包结行为。方法用极谱法考察主体分子β-CD与电活性客体分子辅酶Q10发生包结反应时，包结物还原波峰电流随时间的变化，峰电位随β-CD浓度的变化，并在自然光照条件下分别考察辅酶Q10和包结物的还原波峰电流随时间的变化。结果在0.1 mol·L^-1 HAc/NaAc (pH 4.7)的乙醇-水(60∶40)介质中，辅酶Q10与β-CD形成1∶1的包结物，测得其包结常数kf为1.26×10⁴ L·mol^-1，包结反应的表观速率常数k为6.64×10^-2 min^-1。并测得辅酶Q10的光降解表观速率常数k为7.77×10^-3 min^-1，辅酶Q10-β-CD包结物的k为3.38×10^-3 min^-1。结论辅酶Q10和β-CD可形成包结物，并在一定程度上提高了辅酶Q10的光稳定性。}     

Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis

It has been shown that the hallucinogenic potencies of LSD, the phenylisopropylamines, such as DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) and DOI (4-iodo-2,5-dimethoxyphenylisopropylamine), and the indoleaklylamines, such as DMT (dimethyltryptamine) and 5-OMe-DMT (5-methoxy-dimethyltryptamine), strongly correlate with their in vitro 5-HT₂ receptor binding affinities in rat cortical homogenates. In order to ascertain if this correlation applies to human 5-HT₂ receptors as well, we examined the affinities of 13 psychoactive compounds at ³H-ketanserin-labelled 5-HT₂ receptors in human cortical samples. Both radioligand binding and autoradiographical procedures were used. As in rat brain d-LSD was the most potent displacer of ³H-ketanserin specific binding with a K _i of 0.9 nM. The phenylisopropylamine DOI also displayed high affinity (K _i of 6 nM). Stereospecific interactions were found with DOB; (-_ DOB had a K _i of 17 nM while (+) DOB had a K _i of 55 nM. The behaviorally active compound DOM (4-methyl-2,5-phenylisopropylamine) had an affinity of 162 nM while its behaviorally less active congener iso-DOM had an affinity of 6299 nM. The indolealkylamines 5-OMe-DMT and DMT competed with moderate affinities (207 and 462 nM, respectively). In general, Hill coefficients were significantly less than unity which is consistent with an agonist interaction with 5-HT₂ receptors. MDMA, a substituted amphetamine analog was inactive with a K _i of greater than 10 M. A strong correlation was found for the hallucinogen affinities and human hallucinogenic potencies (r=0.97). Also, human and rat brain 5-HT₂ receptor affinities were strongly correlated (r=0.99). These results strongly support the hypothesis that the hallucinogenic effects of these drugs in humans are mediated in whole or in part via 5-HT₂ receptors. Furthermore, these studies imply that treatment with 5-HT₂ receptor antagonists may be effective in reversing the hallucinogenic effects caused by the ingestion, of LSD and LSD-like drugs.     

Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens

Alterations in brain serotonergic function have been implicated in the mechanism of action of LSD, mescaline, and other similarly acting hallucinogenic drugs of abuse such as STP (2,5-dimethoxyphenylisopropylamine; DOM). In order to test the hypothesis that the mechanism of action of LSD and phenylisopropylamine hallucinogens is through stimulation of a specific brain serotonin receptor sub-type, the affinities of these compounds for radiolabelled 5-HT₂, 5-HT_1A, 5-HT_1B, and 5-HT_1C receptors have been determined using recently developed in vitro radioligand binding methodologies. The 5-HT₂ receptor was labelled with the agonist/hallucinogen radioligand ³H-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine). The 5-HT_1A, 5-HT_1B, and 5-HT_1C receptors were labelled with ³H-OH-DPAT, ³H-5-HT, and ³H-mesulergine, respectively. In general, the phenylisopropylamines displayed 10–100 fold higher affinities for the 5-HT₂ receptor than for the 5-HT_1C receptor and 100–1000 fold higher affinities for the 5-HT₂ receptor than for the 5-HT_1A or 5-HT_1B receptor. There was a strong correlation between hallucinogenic potencies and 5-HT₂ receptor affinities of the phenylisopropylamines (r=0.90); the correlation coefficients for the 5-HT_1A, 5-HT_1B, and 5-HT_1C were 0.73, 0.85, and 0.78, respectively. Because there is no evidence that 5-HT_1A-selective or 5-HT_1B-selective agonists are hallucinogenic and because the phenylisopropylamines are potent hallucinogens, a 5-HT₂ receptor interaction is implicated and supports our previous suggestions to this effect. A secondary role for 5-HT_1C receptors cannot be discounted at this time. These results, when integrated with other receptor pharmacological information, indicate that an important component of the mechanism of action of LSD and the phenylisopropylamine hallucinogens is through stimulation of brain 5-HT₂ receptors. Offprint requests to: M. Titeler     

Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2C receptor

Interactions of the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and its main metabolite norfluoxetine, and the tricyclic anti-depressant (TCA) imipramine with the rat serotonin 5-HT_2C receptor in a clonal cell line and in the rat choroid plexus were investigated by radioligand binding and phosphoinositide (PI) hydrolysis assays. For comparison, the affinities of a variety of other antidepressants of different chemical classes for the cloned rat 5-HT_2C and 5-HT_2A receptors were also determined by radioligand binding assays. Fluoxetine displayed relatively high affinity for the 5-HT_2C receptor in the choroid plexus, with a K_i value for inhibition of [³H]mesulergine binding of 55.4 nM. The K_i values for imipramine, norfluoxetine and citalopram were 136 nM, 203 nM, and 298 nM, respectively. Similar rank order of potency was detected in PI hydrolysis assays, which showed that these drugs are antagonists at the 5-HT_2C receptor without exhibiting inverse agonist activity. [³H]Ketanserin (5-HT_2A) binding assays revealed that the SSRIs fluoxetine, norfluoxetine and citalopram show 10- to 23-fold selectivity for the 5-HT_2C receptor in vitro, whereas the TCA imipramine does not. Many other TCAs also had high to intermediate affinity for both 5-HT_2A and 5-HT_2C receptors. The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT_2C receptor.     

Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285

Summary Three chemical classes of serotonin 5-HT₄ receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT₄ receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3–5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded K_i values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT₃ receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (K_i, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID₅₀, 231 vs 0.5 g/kg, i.v.). No significant binding (K_i>10 mol/l) of DAU 6285 to serotonergic 5-HT_1A, 5-HT_1B, 5-HT_1C, 5-HT_1D, and 5-HT₂ receptors as well as to adrenergic ₁, ₂, dopaminergic D₁, D₂ or muscarinic M₁–M₃ receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT₄ receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT₃ receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT₄ receptors. Send offprint requests to A. Dumuis at the above address     

Cloning,expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7(b))

1. The rat 5-hydroxytryptamine (5-HT)₇ receptor displays two splice variations, a long form, and a truncated splice isoform, arising from the introduction of a stop codon near the carboxy-terminus. The human 5-HT₇ receptor gene contains at least two introns and encodes a 445 amino acid 5-HT receptor.
2. A truncated splice variation in the human 5-HT₇ receptor was isolated from a human placental cDNA library. In accordance with current NC-IUPHAR nomenclature guidelines, it is suggested that this receptor be denoted as the h5-HT_7(b) receptor and the long form of the receptor as h5-HT_7(a).
3. The h5-HT_7(b) receptor was stably expressed in HEK 293 cells and ligand affinities were determined by displacement of [³H]-5-carboxyamidotryptamine (5-CT; K_d=0.28±0.06 nM, B_max=7.3±1.7 pmol mg⁻¹ protein). The rank order of affinities (pK_i) for a series of ligands was: 5-carboxamidotryptamine (5-CT, 9.65)>5-hydroxytryptamine (5-HT, 9.41)>methiothepin (8.87)>mesulergine (7.87)>8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT, 6.85)>ketanserin (6.44).
4. The h5-HT_7(b) receptor coupled positively to adenylyl cyclase in HEK 293 cells. This response was elicited by a number of agonists with the following order of potency (pEC₅₀): 5-CT (8.7±0.11)>5-MeOT (5-methoxytryptamine; 8.1±0.20)>5-HT (7.5±0.13)>tryptamine (5.6±0.36)>8-OH-DPAT (5.3±0.28)>5-methoxytryptamine (5.0±0.06). This rank order was comparable to that observed in the radioligand binding studies.
5. In a similar fashion to that described for the 5-HT_7(a) receptor, PCR studies suggested that the 5-HT_7(b) receptor mRNA is found in great abundance throughout the brain, in the small intestine and aorta.
6. It is concluded that the h5-HT₇ receptor, like the rat receptor, exists as splice variants exhibiting similar pharmacology, signal transduction and distribution. It is thus likely that there exists a complex physiological role for alternate splicing products of the 5-HT₇ receptor gene.

     

BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex

In the search for antidepressant agents with a rapid onset of action, we have found that compound BIMT 17 (1-[2-[4-(3-trifluoromethylphenyl)piperazin1-yl]ethyl]benzimidazol-[1H]-2-one) shows a good affinity for cerebral cortical 5-HT_1A (pK _i = 7.72) and 5-HT_2A (pK _i = 6.90) receptors, with no appreciable affinity for the other 5-HT receptor subtypes, including 5-HT_2C. BIMT 17 reduced forskolin-stimulated cAMP accumulation in the cerebral cortex (pEC₅₀ = 6.09) and in the hippocampus (pEC₅₀ = 6.50), and antagonized 5-HT-induced phosphatidylinositol turnover (pK _i = 6.96) in the cerebral cortex. The effect on cAMP accumulation was blocked by the 5-HT_1A receptor antagonist tertatolol. Buspirone, 8-OH-DPAT and S 14671 {1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphtyl)]piperazine, claimed to be 5-HT_1A receptor agonists, did not reduce forskolin-stimulated cAMP formation in the cerebral cortex.On the basis of these data, it was concluded that BIMT 17 was the only compound that behaved as a full agonist with respect to the CAMP response in the cortex, while exerting concurrent agonism at 5-HT_1A receptors and antagonism at 5-HT_2A receptors. These characteristics might explain the peculiar behaviour of BIMT 17 in mimicking the inhibitory action of 5-HT on the basal firing rate of the cortical neurons (see accompanying paper).     

The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons

Summary We have previously shown that a non-classical 5-hydroxytryptamine (5-HT₄) receptor mediates the stimulation of adenylate cyclase activity in mouse embryo colliculi neurons in primary culture. The pharmacological characteristics of this receptor exclude the possibility that it belongs to the known 5-HT₁, 5-HT₂ or 5-HT₃ receptor types. Here we report that this 5-HT receptor can be stimulated by 4-amino-5-chloro-2-methoxy substituted benzamide derivatives. All these compounds have been reported to be potent stimulants of gastrointestinal motility and some of them are 5-HT₃ receptor antagonists. The rank order of potency of these substituted benzamide derivatives in stimulating cAMP formation was: cisapride > BRL 24924 > 5-HT > zacopride > BRL 20627 > metoclopramide. The non-additivity of benzamide and 5-HT activities suggests that 5-HT and the substituted benzamide derivatives act on the same receptor. Only ICS 205930, a recognized 5-HT₃ receptor antagonist, competitively antagonized the stimulatory effect of cisapride, zacopride and BRL 24924. However, its pK _i (6–6.3) for this new receptor was very different from its pK _i for 5-HT₃ receptors (pK _i = 8 –10). Other selective 5-HT₃ receptor antagonists with an indole group (BRL 43694 and GR 38032F), with a benzoate group (cocaïne, MDL 72222) or with a piperazine group (quipazine) were ineffective in reversing the stimulatory effect of benzamide derivatives. Exposure of neuronal cells to potent agonists at this receptor such as BRL 24924 rapidly reduces its capacity to stimulate cAMP production. For example, a preincubation of 10 min with BRL 24924 (100 mol/l) reduced by 42% the ability of 5-HT to stimulate cAMP production. Cross-desensitization occurs between the effects of 5-HT and benzamides. The unique pharmacology of these nonclassical 5-HT receptors that we propose to call 5-HT₄ is very close and even identical to the pharmacology of the high affinity 5-HT receptors involved in the indirect stimulation of smooth muscle in the guinea pig ileum. These receptors are different from the 5-HT₃ receptors also present in guinea pig ileum.Send offprint requests to A. Dumuis at the above address     

Evidence for mediation by 5-HT2 receptors of 5-hydroxytryptamine-induced contraction of canine basilar artery

Summary The agonist potencies of 8 indole derivatives and the potencies of 19 recognized antagonists to inhibit constrictor responses to 5-hydroxytryptamine (5-HT) of canine basilar artery were established. In addition the affinities of the indole derivatives for [³H]5-hydroxytryptamine ([³H]5-HT) binding sites and the affinities of the antagonists for [¹²⁵Iodo]LSD ([¹²⁵I]LSD) binding sites in rat brain cortex membranes were determined. Comparison was also made between the potencies of the antagonists on canine basilar artery and the K _D values published for displacement of [³H]ketanserin binding (Leysen et al. 1982).There was a good correlation between the affinities of the antagonists for 5-HT₂ binding sites labelled by both [¹²⁵I]LSD and [³H]ketanserin and the affinity parameters calculated for inhibition of constrictor responses to 5-HT of canine basilar artery. No correlation could be found between the affinities of the indole derivatives for 5-HT₁ binding sites labelled by [³H]5-HT and their potencies to constrict canine basilar artery.It is concluded that constrictor responses to 5-HT of canine basilar artery are mediated by 5-HT₂-like receptors.     

On the role of brain 5-HT7 receptor in the mechanism of hypothermia: comparison with hypothermia mediated via 5-HT1A and 5-HT3 receptor

Intracerebroventricular administration of selective agonist of serotonin 5-HT₇ receptor LP44 (4-[2-(methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-pyperasinehexanamide hydrochloride; 10.3, 20.5 or 41.0 nmol) produced considerable hypothermic response in CBA/Lac mice. LP44-induced (20.5 nmol) hypothermia was significantly attenuated by the selective 5-HT₇ receptor antagonist SB 269970 (16.1 fmol, i.c.v.) pretreatment. At the same time, intraperitoneal administration of LP44 in a wide range of doses 1.0, 2.0 or 10.0 mg/kg (2.0, 4.0, 20.0 μmol/kg) did not cause considerable hypothermic response. These findings indicate the implication of central, rather than peripheral 5-HT₇ receptors in the regulation of hypothermia. The comparison of LP44-induced (20.5 nmol) hypothermic reaction in eight inbred mouse strains (DBA/2J, CBA/Lac, C57BL/6, BALB/c, ICR, AKR/J, C3H and Asn) was performed and a significant effect of genotype was found.In the same eight mouse strains, functional activity of 5-HT_1A and 5-HT₃ receptors was studied. The comparison of hypothermic responses produced by 5-HT₇ receptor agonist LP44 (20.5 nmol, i.c.v.) and 5-HT_1A receptor agonist 8-OH-DPAT 1.0 mg/kg, i.p. (3.0 μmol/kg), 5-HT₃ receptor agonist m-CPBG (40.0 nmol, i.c.v.) did not reveal considerable interstrain correlations between 5-HT₇ and 5-HT_1A or 5-HT₃ receptor-induced hypothermia. The selective 5-HT₇ receptor antagonist SB 269970 (16.1 fmol, i.c.v.) failed to attenuate the hypothermic effect of 8-OH-DPAT 1.0 mg/kg, i.p. (3.0 μmol/kg) and m-CPBG (40.0 nmol, i.c.v.) indicating that the brain 5-HT₇ receptor is not involved in the hypothermic effects of 8-OH-DPAT or m-CPBG. The obtained results suggest that the central 5-HT₇ receptor plays an essential role in the mediation of thermoregulation independent of 5-HT_1A and 5-HT₃ receptors.