6β－乙酰氧基去甲托烷呼吸抑制效应

６β－乙酰氧基去甲托烷（６β－ａｃｅｔｏｘｙｎｏｒｔｒｏｐａｎｅ，６β－ＡＮ）是一种新型Ｍ２受体激动剂，兔１０ｕｇ·ｋｇ－１ｉｖ，犬２，５，２０ｕｇ·ｋｇ－１ｉｖ均导致呼吸频率、潮气量、每分通气量明显减少（Ｐ＜０．０５或０．０１），呈剂量依赖关系。ｐＯ２降低，ｐＣＯ２升高。较小剂量给兔０．５，１．０，２．０，４．０ｕｇ·ｋｇ－１ｉｖａ和犬０．２５，０．５，１．０ｕｇ·ｋｇ－１ｉｖａ亦产生与静脉给药相似的呼吸抑制效应。ＡＦ－ＤＸ１１６能拮抗６β－ＡＮ的呼吸抑制作用，ＰＺ则与６β－ＡＮ产生协同作用。表明６β－ＡＮ有呼吸抑制作用，并可能与其激动呼吸中枢Ｍ２受体有关。     

6β-乙酰氧基去甲托烷呼吸抑制效应

6β-乙酰氧基去甲托烷(6β-acetoxynortropane,6β-AN)是一种新型M2受体激动剂,兔10ug·kg^-1iv,犬2,5,20ug·kg^-1iv均导致呼吸频率、潮气量、每分通气量明显减少(P<0.05或0.01),呈剂量依赖关系。pO₂降低,pCO₂升高。较小剂量给兔0.5,1.0,2.0,4.0ug·kg^-1iva和犬0.25,0.5,1.0ug·kg^-1iva亦产生与静脉给药相似的呼吸抑制效应。AF-DX116能拮抗6β-AN的呼吸抑制作用,PZ则与6β-AN产生协同作用。表明6β-AN有呼吸抑制作用,并可能与其激动呼吸中枢M2受体有关。     

苯甲酰胺类抗精神病药物的研究:若干3α-去甲托品烷衍生物的合成

Reductive amination of8- benzyl-nortropinone(3 )with ammonium acetate andsodium cyanoborohydride yielded the 3 α-amino nortropane derivative 4 which was condensed withsubstituted benzoic acids using 2-bromo-N-methyl-pyridinium iodide as condensing reagent to give thetarget compounds 2a～ein an overall yield of 50～60%.Compound 2e showed marked and selectiveaffinity for D-2 receptor.Compound 2d showed definite affinity for D- 1 receptor besides markedaffinity for D-2 receptor.     

苯甲酰胺类抗精神病药物的研究：若干3α－去甲托品烷衍生物的合成

苯甲酰胺类抗精神病药物的研究：若干３α－去甲托品烷衍生物的合成褚国华，周启霆（上海中国科学院上海药物研究所２０００３１）在治疗精神病的药物中，有一类称为苯甲酰胺类抗精神病药物。其分子结构可用如下通式表示，特点为分子中含叔胺及苯甲酰胺单元，其间嵌入各种...     

苯甲酰胺类抗精神病药物的研究:6β-羟基,乙酰氧基和苯甲酰氧基-3α及β-托品烷衍生物的合成

合成了15个3α和β-取代苯申酰氨基-6β-羟基,乙酰氧基和苯甲酰氧基-托品烷类化合物。其中化合物5d,12c和12d对D-1和D-2受体都有一定的亲和作用。     

苯甲酰胺类抗精神病药物的研究：6β－羟基，乙酰氧基和苯甲酰氧基－3α及β－托品烷衍生物的合成

合成了１５个３α和β－取代苯申酰氨基－６β－羟基，乙酰氧基和苯甲酰氧基－托品烷类化合物。其中化合物５ｄ，１２ｃ和１２ｄ对Ｄ－１和Ｄ－２受体都有一定的亲和作用。     

黄体酮对离体豚鼠呼吸道平滑肌的作用

黄体酮能明显抑制由乙酰胆碱、组织胺和5—羟色胺所致的离体豚鼠气管、肺条平滑肌的收缩反应,对由5—羟色胺诱发的气管平滑肌依内钙释放引起的！相收缩有非常显著的抑制作用,并能抑制致敏豚鼠气管平滑肌schultZ—Dale反应.关键词黄体酮,维拉帕米,慢反应物质,呼吸道平滑肌     

胶束色谱法分析莨菪生药中托烷生物碱的研究

本文建立了胶束高效液相色谱法,在氰基柱上,以甲醇为改性剂,二十烷基硫酸钠为表面活性剂,采用改良单纯形法优化色谱条件,优选出不仅能分离莨菪生药中莨菪碱,东莨菪碱、山莨菪碱和樟柳碱等四种托烷生物碱,并能同时分离生物碱与生药中其它干扰组分的色谱条件。在选定的流动相下经临界胶束浓度测定及分离机理考察,确定为胶束色谱。应用所建立的方法,测定了唐古特山莨菪等几种药材中上述四种托烷生物碱的含量。     

消旋山莨菪碱及其片剂中托烷生物碱的鉴别

目的对中国药典收载的消旋山莨菪碱片的托烷生物碱基团的鉴别试验提出修改建议。方法将消旋山莨菪碱片剂及其原料药的鉴别试验与药典附录Ⅲ(一般鉴别试验)中有关托烷生物碱类的鉴别试验进行比较、分析。结果消旋山莨菪碱片剂与原料药及附录中有关托烷生物碱基团的鉴别试验方法存在不一致之处。结论应对消旋山莨菪碱片剂鉴别方法进行修订。     

Contractile effect of succinylpurines on guinea pig uterus

1. The effects of adenosine analogues on isolated guinea pig uterus were studied in vitro. 2. Low concentrations of adenosine analogues contracted guinea pig uterus. The relative potencies of contractive effect were adenosine greater than AMP greater than ADP greater than ATP greater than 2-chloroadenosine greater than N6-phenylisopropyl-adenosine (PIA) greater than 5'-N-ethylcarboxamidoadenosine (NECA) greater than adenylosuccinate greater than succinyladenosine. 3. Pretreatment of the uterus strips with theophylline blocked the action of adenosine. However, dipyridamole did not impair the adenosine actions. 4. The role of naturally occurring adenosine analogues was discussed.     

Contractile effect of prolactin on guinea pig isolated ileum

Prolactin (PRL) at high concentrations contracted the guinea pig isolated ileum. The maximum response elicited by PRL was 44% of that of histamine-induced responses. There was no significant difference in potency between PRL preparations obtained from two different sources. PRL responses were nullified by denaturation or proteolytic digestion of the hormone. The contractile response was antagonised by atropine and potentiated by neostigmine, but unaffected by the prostaglandin antagonist SC-19220. The pA2 values of atropine against PRL and ACh were similar. Preincubation with morphine, which inhibits ACh release, produced slight inhibition of PRL-evoked contractions. Even high concentrations of PRL failed to produce any response in neostigmine-treated frog rectus muscle preparations. This suggests that PRL may produce contractions through a cholinergic mechanism involving muscarinic receptors. Enhanced gut motility reported earlier for hyperprolactinemic states may be attributed to this cholinomimetic effect of PRL on the intestinal tract.     

Atypical effect of minoxidil sulphate on guinea pig airways

The effects of minoxidil sulphate, an "atypical" K(ATP) channel opener, and bimakalim, a benzopyran-type classical K(ATP) channel opener, on guinea pig airways in vitro and in vivo and on isolated portal veins from rats and guinea pigs were compared. Minoxidil sulphate inhibited the spontaneous activity of isolated guinea pig and rat portal vein preparations with pD2 values of 7.83+/-0.08 and 7.14+/-0.03, respectively (Emax=100% in both preparations). Bimakalim caused a more potent inhibition with pD2 values of 8.80+/-0.05 and 8.20+/-0.04, respectively (Emax=100% in both preparations). Minoxidil sulphate reduced the spontaneous tone of isolated guinea pig tracheal rings with a pIC50 value of 3.92+/-0.02 and the same efficacy as isoprenaline. Bimakalim was more potent (pIC50=7.25+/-0.02) but less efficacious (Emax=75% of the Emax of isoprenaline). The airway relaxant effect of bimakalim, but not minoxidil sulphate, was antagonised by glibenclamide (pA2=7.50) at concentrations above 0.1 microM. Bombesin-induced bronchoconstriction in anaesthetised, ventilated, normoreactive guinea pigs (measured as increase in total lung resistance) was dose-dependently reversed by intratracheally (i.t.) administered bimakalim (ED50=4 microg/kg; Emax=92% of maximally possible inhibition), but not by minoxidil sulphate, at doses up to 1 mg/kg i.t. In the same animals, following i.t. administration of higher doses, both minoxidil sulphate and bimakalim reduced blood pressure. Airways hyperreactivity to histamine induced by acute treatment of guinea pigs with immune complex was dose-dependently reversed by bimakalim (ED50=0.5 microg/kg i.t., Emax=100%). This effect was antagonised by glibenclamide (30 mg/kg i.v.). Minoxidil sulphate had a biphasic effect on airways hyperreactivity: at 1 microg/kg i.t., airways hyperreactivity was augmented, whereas at doses above 3.2 microg/kg i.t. it caused reversal of airways hyperreactivity. Both of the effects of minoxidil sulphate were insensitive to glibenclamide (30 mg/kg i.v.). It is concluded that the pharmacological profile of minoxidil sulphate in guinea pig airways is completely different from that of classical K(ATP) channel openers such as bimakalim. Minoxidil sulphate is either only weakly active or even inactive at K(ATP) channels in guinea pig airways or interacts with these channels in a different manner. The current results are consistent with there being differences between the K(ATP) channels in airways and blood vessels.     

Effects of ATP and VIP on guinea pig airways

The bronchodilator effects of vasoactive intestinal peptide (VIP) and adenosine triphosphate (ATP), putative neurotransmitters of nonadrenergic, noncholinergic innervation, were compared with those of isoproterenol (ISP) in guinea pig airways by in vivo and in vitro techniques. In both studies, the test agents produced dose-dependent relaxations. The response of airway smooth muscle to ISP was significantly greater than the responses to the test agents. In the in vivo studies, the test agents produced statistically equieffective responses. However, in the in vitro studies, VIP produced complete relaxation of the precontracted tissues to the baseline, whereas ATP could not, suggesting VIP as a more effective relaxant than ATP.     

Contractile response of guinea pig ileum by repetitive application of morphine.

1. The repetitive application of morphine gradually induced a contracture in the isolated guinea pig ileum. 2. The optimum conditions for induction of the contracture were as follows: the concentration, incubation time and washout time of morphine were 1 or 10 microM, 2 and 3 min, respectively. 3. Preincubation with naloxone or TTX blocked this morphine-induced contracture. 4. Among twitch-inhibiting drugs, only clonidine induced a contracture similar to that induced by morphine, while tetrodotoxin (TTX) and adenosine did not. 5. The contracture was also observed in the longitudinal muscle-myenteric plexus preparations. 6. These findings indicate that morphine has a dual inhibitory and excitatory action on the guinea pig ileum and that its repetitive application preferentially diminish the inhibitory one.     

Inflammatory cell influx into ozone-exposed guinea pig lung interstitial and airways spaces.

As a model of non-immunological lung inflammation, guinea pigs were exposed to 2.0 ppm ozone for 4 hours. Polymorphonuclear leukocytes (PMNs) rapidly accumulated in lung interstitium but declined from 147 +/- 34 million cells to control values (33 +/- 6 million cells) within the first 24 hours. Bronchoalveolar lavage (BAL) recovered PMNs were maximal by 3-6 hours (4 +/- 1 million cells) and remained elevated for 3 days. Macrophage numbers were doubled in lavageable spaces but those in interstitium increased by only a third at 2 days post-exposure. By 7 days post-exposure BAL macrophages had declined to control values of 12 +/- 2 million cells while those in interstitium remained elevated through 14 days. These data demonstrate that BAL does not necessarily reflect cellular changes in lung interstitium.     

In vitro and in vivo effects of SCA40 on guinea pig airways

SCA40 (6-bromo-8-methylaminoimidazo[1,2-a]- pyrazine-2-carbonitrile), a compound which had been described as an opener of Ca²⁺-dependent large conductance potassium channels (BK_Ca channels), was investigated in comparison with salbutamol for in vitro and in vivo bronchospasmolytic effects and for the ability to reverse airways hyperreactivity in guinea pigs. SCA40 reduced the spontaneous tone of isolated guinea pig tracheal rings with a biphasic concentration-response curve (first phase: pD₂ = 8.0, E_Max = 29.7% of maximal effect; second phase: pD₂ = 6.4, E_Max = 72.6%). The salbutamol curve was monophasic (pD₂ = 8.0, E_Max = 100%). Total lung resistance (R_L) was determined in anaesthetized, ventilated guinea pigs. Bronchoconstriction, measured as an increase in R_L, was elicited in normoreactive animals by i.v. infusion of bombesin (100 ng/kg/min) or by i.v. injection of histamine (1.8–5.6 μg/kg). Airways hyperreactivity was induced by acute i.v. administration of pre-formed immune complexes. Intravenous bolus injections of histamine (2.4 μg/kg) were used to define the sensitivity of the airways prior to and after the exposure to immune complex. Following intratracheal (i.t.) administration, SCA40 reversed bombesin-induced bronchoconstriction with an ED₅₀ of 43 μg/kg (E_Max = 57%). The ED₅₀ for salbutamol was 0.8 μg/kg i.t. (E_Max = 78%). Histamine-induced bronchoconstriction in hyperreactive guinea pigs was inhibited by SCA40 with an ED₅₀ of 13 μg/kg i.t. (E_Max = 82%). Salbutamol completely inhibited histamine-induced bronchospasm with an ED₅₀ of 9 ng/kg i.t. In normoreactive guinea pigs, SCA40 prevented histamine-induced bronchoconstriction with an ED₅₀ of 100 μg/kg i.t.; for salbutamol the ED₅₀ in this test was 0.48 μg/kg i.t. Thus, for both SCA40 and salbutamol, the effects obtained at low doses in hyperreactive guinea pigs represent a true reversal of airways hyperreactivity, whereas at higher doses, anti-hyperreactive and bronchospasmolytic properties may account for the observed effects. In conclusion, SCA40 relaxes guinea pig airways smooth muscle in vitro and in vivo, and it partly reverses airways hyperreactivity. With respect to both potency and efficacy, SCA40 is markedly less active than the β-adrenoceptor agonist salbutamol. Received: 23 August 1996 / Accepted: 11 October 1996     

痛啡肽抑制豚鼠气道兴奋性非肾上腺素能非胆碱能反应

目的:研究痛啡肽(Nociceptin,NC)及U-50488H对豚鼠离体支气管环的非肾上腺素能非胆碱能兴奋(eNANC)所致收缩的抑制作用。方法:记录电场刺激及辣椒素引起标本eNANC反应的收缩张力,了解NC及U-50488H的作用。结果:NC 0.001-0.1μmol·L~(-1)可抑制标本的eNANC收缩。与对照组相比,NC 0.01μmol·L~(-1)抑制收缩达(43±31)％;预用纳洛酮0.1μmol·L~(-1)后,NC仍抑制收缩达(46±28)％。IC_(50)(95％可信限)是6.12(3.8-9.9)nmol·L~(-1)。U-50488H 0.01 -1μmol·L~(-1)可抑制eNANC收缩,其IC_(50)(95％可信限)为1.08(0.5-2.2)μmol·L~(-1),但是U-50488H 0.1μmol·L~(-1)的抑制作用可被纳洛酮0.1μmol·L~(-1)完全取消。辣椒素0.01-1μmol·L~(-1)可引起eNANC收缩,NC 0.01μmol·L~(-1)和U-50488H 0.1μmol·L~(-1)均不能明显影响辣椒素的作用。外源性神经激肽A 0.01μmol·L~(-1)引起的收缩不受NC和U-50488H 0.1μmol·L~(-1)的影响。结论:NC非纳洛酮敏感地抑制电场刺激引起的豚鼠气道eNANC反应;U-50488H通过激动阿片受体而抑制电场刺激引起的豚鼠气道eNANC反应。