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Query: CAS:82184-71-2 (2-hydroxyethyl)
 4,555 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study evaluates the hypothesis that opiates suppress pancreatic enzyme secretion by inhibiting cholinergic transmission in the pancreas. Rat pancreatic lobules were incubated in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-Ringer's buffer and amylase release in response to KCl depolarization of the intrapancreatic nerve in the absence or presence of specific opiate subtype receptor agonists was studied. Depolarization by 75 mM KCl resulted in a 5-fold increase in amylase output. Pretreatment with 1 microM atropine inhibited completely the KCl-stimulated amylase release, suggesting stimulation via a cholinergic pathway. Addition of methionine enkephalin or 2-D-penicillamine-5-D-penicillamine-enkephalin [( D-Pen2, D-Pen5]enkephalin, a specific delta receptor agonist) inhibited KCl-stimulated amylase release in a dose-dependent fashion. Methionine enkephalin (1 microM) or [D-Pen2, D-Pen5]enkephalin inhibited KCl-stimulated amylase release by 32 +/- 4 and 45 +/- 4%, respectively. Addition of 1 microM ICI 174,864 (a delta opiate receptor antagonist) blocked the inhibitory effect of [D-Pen2, D-Pen5]enkephalin. Upjohn 50,488H (1 microM, a specific kappa agonist) and 1 microM Tyr-D-Ala-Gly-MePhe-Gly-ol (a specific mu agonist) had no effect. Methionine enkephalin had no effect on carbachol (1 microM)-stimulated amylase release. These data suggest that methionine enkephalin acts on a delta opiate receptor located on postganglionic cholinergic neurons. To examine the ability of methionine enkephalin to alter acetylcholine release from pancreatic tissue, pancreatic lobules were incubated with [3H]choline and the release of synthesized [3H]acetylcholine was stimulated by KCl. Depolarization of the nerves with 75 mM KCl increased [3H]acetylcholine release by 35 +/- 5% over basal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of exocrine pancreatic secretion by opiates is mediated by suppression of cholinergic transmission: characterization of receptor subtypes. 245 87

The synthesis of 16 new N10-propargylquinazoline antifolates with methylamino, ethylamino, (2-aminoethyl)amino, [2-(dimethylamino)ethyl]amino, (2-hydroxyethyl)amino, (carboxymethyl)amino, dimethylamino, imidazol-1-yl, methoxy, ethoxy, phenoxy, 2-methoxyethoxy, 2-hydroxyethoxy, mercapto, methylthio, and chloro substituents at C2 is described. In general, the synthetic route involved the coupling of diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate (5a) with 6-(bromomethyl)-2-chloro-3,4-dihydro-4-oxoquinazoline in N,N-dimethylformamide with calcium carbonate as the base, displacement of the C2-chloro substituent with nitrogen and sulfur nucleophiles, and deprotection using mild alkali. The C2-ether analogues were most conveniently prepared by coupling 5a with 6-(bromomethyl)-2,4-diakoxy(or diphenoxy)quinazolines. In this series the final deprotection step with aqueous alkali gave simultaneous selective hydrolysis of the C4-alkoxy or C4-phenoxy substituent. The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS). As a measure of cytotoxicity, they were examined for their inhibition of the growth of L1210 cells in culture. The C2-methoxy analogue 11a was equivalent to the previously described tight binding TS inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717, ICI 155387, 1a) against the TS enzyme and exhibited enhanced potency in culture. The C2-methoxy substituent also gave a 110-fold enhancement in aqueous solubility relative to the C2-amine. These results suggest that 11a will be an interesting compound for further study as a potential antitumor agent in vivo. A further series of 2-methoxyquinazoline antifolates with modified alkyl substituents at N10 is also described. None of these analogues equalled the activity of 11a. Thus the propargyl group appears to be the optimum N10 substituent in both 2-amino- and 2-methoxyquinazoline antifolates.
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PMID:Quinazoline antifolate thymidylate synthase inhibitors: nitrogen, oxygen, sulfur, and chlorine substituents in the C2 position. 291 3

The permeability of bovine pulmonary artery endothelial (CPAE) monolayers to Evans blue-labelled albumin (Evans blue-albumin) has been measured in vitro. Thrombin caused a concentration-dependent increase in Evans blue-albumin clearance across endothelial monolayers. Isoprenaline inhibited thrombin-induced Evans blue-albumin clearance in a concentration-dependent manner (EC50 21 nM). This effect was mimicked by the selective beta 2-adrenoceptor agonists salbutamol (EC50 64 nM) and salmeterol (EC50 2.7 nM), but not by the selective beta 1-adrenoceptor agonist, RO-363 ((1-[3',4'-dihydroxyphenoxy]-2-hydroxy-[3",4"- dimethoxyphenethylamino]-propane)oxalate), nor by the selective beta 3-adrenoceptor agonist, CL-316,243 (disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3- benzodioxole-2,2-dicarboxylate). Isoprenaline, salbutamol and salmeterol, but not RO-363 or CL-316,243 produced small, but significant reductions in Evans blue-albumin clearance across unstimulated endothelial monolayers. Inhibition of the response to thrombin by isoprenaline was antagonised by the selective beta 2-adrenoceptor antagonist, ICI-118,551 ((erythro-DL-1(7-methylindan-4- yloxy)3-isopropylaminobutan-2-ol), pKB 8.4). Salmeterol also inhibited hydrogen peroxide-stimulated Evans blue-albumin clearance. Hence, the widely used beta 2-adrenoceptor agonists, salbutamol and salmeterol, are able to reduce endothelial permeability at nanomolar concentrations.
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PMID:Beta 2-adrenoceptors mediate a reduction in endothelial permeability in vitro. 776 83

The beta-3 adrenoceptor protein lacks most of the potential phosphorylation sites for beta adrenoceptor kinase and protein kinase A. In addition, it exhibits a lower affinity toward norepinephrine than beta-1 or beta-2 adrenoceptors. It is thus expected that beta-3 adrenoceptors could be less implicated in desensitization processes than the beta-1 or beta-2 adrenoceptors. An attempt to demonstrate the physiological relevance of this prediction was performed by using fat cells having a beta-3 adrenergic responsiveness or not (hamster and guinea pig). The influence of prolonged in vivo exposure to norepinephrine on the beta adrenoceptor-mediated lipolytic responses was investigated in both species. In control guinea pigs, isoproterenol, norepinephrine and epinephrine were fully lipolytic, whereas BRL 37344 [(R',R')-4-2[2-((2[(3-chlorophenyl)-2-hydroxyethyl]amino] propyl)phenyl]phenoxyacetic acid], CGP 12177](+-)-4-(3-tertiarybutylamino-2-hydroxypropoxy)- benzimidazole-2-on hydrochloride] and other beta-3 agonists were inefficient, whereas hamster adipocytes exhibited maximal response to the beta-3 agonists. Blockade of the lipolytic effect of isoproterenol in the guinea pig gave a rank order of beta antagonists [CGP 20712A (1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-4-(1-methyl-4-tr i-fluoro-methyl-1H-imidazol-2-yl)phenoxy-2-propanol methanesulfonate] > bupranolol > or = propranolol >> ICI 118551 [erythrodl-1-(7- methylindan-4-yloxy)-3-isopropylaminobutan-2-ol)] in agreement with that of a beta-1 effect. In contrast, the selective beta-1 antagonist CGP 20712A did not counteract the effect of BRL 37344 in hamsters and bupranolol was the best beta antagonist tested; a result arguing for the predominance of a beta-3 component in the adrenergic activation of lipolysis, as in rat fat cells. In treated guinea pigs (6-day treatment with osmotic minipumps delivering norepinephrine at the rate of 5 micrograms/min/kg), the adrenocorticotropic hormone dose-response curve was identical to that of controls, but the curves for isoproterenol, norepinephrine and epinephrine were flattened and shifted to the right. A down-regulation of beta-1 and beta-2 adrenoceptors was evidenced by a reduction in [3H]CGP 12177 high-affinity binding sites. In treated hamsters, compared to the controls, there was no change in the lipolytic response to the beta adrenergic agonists. Other protocols of chronic exposure to norepinephrine (e.g., daily injections) at different doses were also unable to reduce the beta-lipolytic effect in the hamster fat cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Desensitization of beta-1 and beta-2, but not beta-3, adrenoceptor-mediated lipolytic responses of adipocytes after long-term norepinephrine infusion. 809 43

The beta 3-adrenoceptor (beta 3-AR) agonist SR-58611A {ethyl-[(7s)-7-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]5, 6,7,8-tetrahydronaphth-2-yl]oxyacetate hydrochloride} stimulated somatostatin and gastrin releases in isolated rat gastric antral epithelial cells. Stimulation was a concentration-dependent process with 50% effective concentrations of 2.7 +/- 1.1 and 3.8 +/- 1.9 nM compared with 209 +/- 71 and 230 +/- 51 nM for isoproterenol, respectively. It was inhibited by selective beta-AR antagonists with the following rank order of potency: SR-59230A 3-(2-ethylphenoxy)1-[(1S)-1,2,3,4-tetrahydronaphth- 1-ylamino]-(2S)-2-propranol oxalate; beta 3-AR antagonist > ICI-118551[erythro-(+/-)-1-(7-methylindan-4-yloxy)-3- isopropylaminobutan-2-ol-hydrochloride; beta 2-AR antagonist > CGP-20712A[(+/-)-[2-(3-carbarmoyl-4-hydroxyphenoxy)-et hyl- amino]-3-[4 (1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]- 2-propranol; beta 1-AR antagonist]. Furthermore, specific binding of 125I-cyanopindolol to the isolated cells was demonstrated and was displaced by the beta-AR antagonists according to the same rank order of potency and with apparent dissociation constants consistent with the 50% inhibitory concentrations for SR-58611A-stimulated somatostatin and gastrin releases. In addition, the presence of beta 3-AR mRNA was detected by reverse transcriptase polymerase chain reaction. These findings provide the first evidence for a gastric beta 3-AR mediating catecholamine stimulation of gastrin and somatostatin releases from antral cells.
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PMID:Characterization of a beta 3-adrenoceptor stimulating gastrin and somatostatin secretions in rat antrum. 917 7

Numerous synthetic agonists selectively stimulate beta3-adrenoceptors (ARs). The endogenous catecholamines, noradrenaline and adrenaline, however, stimulate all the beta-AR subtypes, and no selective physiological agonist for beta3-ARs has been described so far. The aim of this study was to investigate whether any naturally occurring amine can stimulate selectively beta3-ARs. Since activation of lipolysis is a well-known beta-adrenergic function, the efficacy and potency of various biogenic amines were compared with those of noradrenaline, isoprenaline, and beta3-AR agonists 4-(-{[2-hydroxy-(3-chlorophenyl)ethyl]-amino} propyl)phenoxyacetate (BRL 37,344) and (R,R)-5-(2-{[2-(3-chlorophenyl )-2-hydroxyethyl]-amino} propyl)-1,3-benzo-dioxole-2,2-dicarboxylate (CL 316,243) by testing their lipolytic action in white fat cells. Five mammalian species were studied: rat, hamster and dog, in which selective beta-AR agonists act as full lipolytic agents, and guinea-pigs and humans, in which beta3-AR agonists are less potent activators of lipolysis. Several biogenic amines were inefficient (e.g. dopamine, tyramine and beta-phenylethylamine) while others (synephrine, phenylethanolamine, epinine) were partially active in stimulating lipolysis in all species studied. Their actions were inhibited by all the beta-AR antagonists tested, including those selective for beta1- or beta2-ARs. Octopamine was the only amine fully stimulating lipolysis in rat, hamster and dog fat cells, while inefficient in guinea-pig or human fat cells, like the beta3-AR agonists. In rat white fat cells, beta-AR antagonists inhibited the lipolytic effect of octopamine with a relative order of potency very similar to that observed against CL 316,243. Competitive antagonism of octopamine effect resulted in the following apparent pA2 [-log(IC50), where IC50 is the antagonist concentration eliciting half-maximal inhibition] values: 7.77 (bupranolol), 6.48 [3-(2-ethyl-phenoxy)-1[(1 S)-1,2,3,4-tetrahydronaphth-1-ylaminol]-(2S)2-propanol oxalate, SR 59230A, a beta3-selective antagonist], 6.30[erythro-D,L-1(7-lethylindan-4-yloxy)-3-isopropylamino-+ ++butan-2-ol, ICI 118,551, a beta2-selective antagonist] and 4.71 [(+/-)-[2-(3-carbomyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1- methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]2-propanolmethane sulphonate, CGP 20712A, a beta1-selective antagonist]. Octopamine had other properties in common with beta3-AR agonists: stimulation of oxygen consumption in rat brown fat cells and very low affinity in displacing [3H]CGP 12,177 binding to [beta1- or beta2-ARs in dog and rat adipocyte membranes. In Chinese hamster ovary (CHO) cells expressing human beta3-ARs, octopamine inhibited [125I]ICYP binding with only twofold less affinity than noradrenaline while it exhibited an affinity around 200-fold lower than noradrenaline in CHO cells expressing human beta1- or beta2-ARs. These data suggest that, among the biogenic amines metabolically related to catecholamines, octopamine can be considered as the most selective for beta3-ARs.
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PMID:Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells. 1034 30

In the present study, the beta-adrenoceptor subtypes distributed in the detrusor of the ferret were investigated in functional experiments in vitro and in vivo using a variety of beta-adrenoceptor agonists and antagonists. All the beta-adrenoceptor agonists tested relaxed the isolated detrusor strip, the rank order of potency being (+/-)-(R*, R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]phenoxy]- acetic acid sodium (BRL 37344A)>(+/-)-4-(3-t-butylamino-2-hydroxypropoxy) benzimidazol-2-one (CGP-12177A), isoprenaline and (R, R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1, 3-benzodioxole-2,2-dicarboxylate (CL 316,243)>dobutamine and procaterol. In antagonist experiment, 3-(2-allylphenoxy)-1-[(1S)-1,2, 3,4-tetrahydro-naphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR 58894A), but neither 2-hydroxy-5(2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1H-imidaz ole-2-yl)-phenoxy)propyl)amino)ethoxy)-benzamide monomethane sulphonate (CGP-20712A) nor erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminob utan-2-ol hydrochloride (ICI-118,551), caused a rightward shift of the concentration-relaxation curve for isoprenaline. In in vivo experiments, isoprenaline and CL 316,243 each reduced bladder pressure in a dose-dependent manner. CL 316,243 was the only drug that did not produce any significant influences on blood pressure and heart rate at doses that reduced bladder pressure. The present functional study provides the first evidence that relaxation of the ferret detrusor by beta-adrenoceptor activation is mediated mainly via the beta(3)-adrenoceptor, as in the human detrusor.
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PMID:Characterization of beta-adrenoceptor subtypes in the ferret urinary bladder in vitro and in vivo. 1096 56

To compare the inhibition of uterine contractility mediated by beta-adrenoceptors and 5-HT(7) receptors, the effects of catecholamines and 5-HT on spontaneous contractions were examined in longitudinal and circular muscles isolated from three different regions (cornu, corpus and cervix) of the non-pregnant proestrus porcine uterus. In addition, the distribution of beta-adrenoceptors between muscle layers was characterized by means of adenylate cyclase activity assay, cyclic AMP assay and [(3)H]dihydroalprenolol binding studies. In the cornu, isoprenaline, adrenaline and noradrenaline inhibited the spontaneous contraction of longitudinal and circular muscles but longitudinal muscle was more sensitive to catecholamines than was circular muscle. The inhibitory response to isoprenaline was antagonized by propranolol (300 nM) or (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551; 100 nM). The rank order of potency was isoprenaline > or =adrenaline > noradrenaline. The beta(2)-adrenoceptor-selective agonist, clenbuterol, was more potent than xamoterol (beta(1)-selective) and (+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid (BRL 37344; beta(3)-selective) to inhibit the spontaneous contraction of longitudinal muscles. Isoprenaline increased adenylate cyclase activity in both muscle layers, but the activity in the longitudinal muscle was greater than that in the circular muscle. Cyclic AMP production by isoprenaline was also more conspicuous in the longitudinal muscle than in the circular muscle. Although both muscle layers contained a single class of [3H]dihydroalprenolol binding sites with similar K(d) values (longitudinal muscle, 3.1+/-0.94 nM, n=4; circular muscle, 2.4+/-0.73 nM, n=4), B(max) in the longitudinal muscle (175.7+/-32.8 fmol/mg protein, n=4) was significantly higher than that in the circular muscle (53.1+/-5.1 fmol/mg protein, n=4). As previously reported [Br. J. Pharmacol. 130 (2000) 79], 5-HT also inhibited the spontaneous contraction of both muscle layers from the cornu and the 5-HT(7) receptor antagonist, 2a-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,5-tetrahydro-benzo[cd]indol-2(1H)-one (DR4004; 100 nM, n=4) blocked the 5-HT-induced inhibition of spontaneous contractions in the circular muscles, and reversed the less marked inhibition in the longitudinal muscles. In other regions of the uterus (corpus and cervix), 5-HT inhibited the spontaneous contraction of the circular muscles but contracted the longitudinal muscle strips. On the other hand, isoprenaline caused muscle layer-dependent inhibition (longitudinal muscle > circular muscle) in both regions, and the responsiveness tended to increase toward the cervix. In conclusion, beta(2)-adrenoceptors are present heterogeneously in the porcine uterus (longitudinal muscle > circular muscle) and share the inhibition of uterine contractility with 5-HT(7) receptors in a layer-dependent manner (longitudinal muscle: beta(2)-adrenoceptors, circular muscle: 5-HT(7) receptors).
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PMID:5-HT(7) receptor and beta(2)-adrenoceptor share in the inhibition of porcine uterine contractility in a muscle layer-dependent manner. 1175 52

Brain tryptophan concentrations are increased by various stressful treatments, an effect that can be prevented by beta-adrenoceptor antagonists. This study aimed to determine the beta-adrenergic subtype responsible for the tryptophan response. Male CD-1 mice received intraperitoneal injections of nonselective and subtype-selective beta-adrenergic antagonists 20 min before subtype-selective beta-agonists. Selected brain regions were dissected for analysis of tryptophan content by high-performance liquid chromatography with electrochemical detection. The beta(2)-selective agonist clenbuterol (0.3 mg/kg) induced increases in brain tryptophan that reached a peak ( approximately 60%) 1 h following injection and small but statistically significant increases ( approximately 20%) in 5-hydroxyindoleacetic acid: serotonin ratios 2 h following injection. The beta(1)-selective agonist dobutamine (10 mg/kg) produced less robust increases ( approximately 40%) in brain tryptophan, whereas the beta(3)-selective agonists BRL 37344 (0.2 mg/kg (+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl] phenoxy]acetic acid sodium)) and CL 316243 [0.1 mg/kg disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate)] resulted in larger increases (80 to 100%). Pretreatment with the beta(2)-selective antagonist ICI 118551 (0.5 mg/kg (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[(1-methylethyl)amino]-2-butanol) attenuated the increases in tryptophan induced by both clenbuterol (0.1 mg/kg) and dobutamine (10 mg/kg). Pretreatment with the beta(1/2)-selective antagonist propranolol (2.5 mg/kg), the beta(3)-selective antagonist SR 59230A [1.5, 2.5, 5, or 20 mg/kg (3-(2-ethylphenoxy)-1[1S)-1,2,3,4-tertahydronaphth-1-yl-amino]-(2S)-2-propanol oxalate)], or ICI 118551 (0.5 mg/kg) did not prevent the BRL 37344-induced increase in brain tryptophan, whereas the beta(1/2/3)-antagonist bupranolol (10 mg/kg) attenuated it. CL 316243 had no effect on brain tryptophan in beta(3)-receptor knockout mice, whereas clenbuterol increased brain tryptophan, indicating that beta-adrenergic modulation of brain tryptophan occurs in the absence of beta(3)-receptors. We conclude that activation of either beta(2)- or beta(3)-adrenergic receptors, but not beta(1)-adrenergic receptors, increases mouse brain tryptophan content.
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PMID:Activation of beta2- and beta3-adrenergic receptors increases brain tryptophan. 1260 31

The present study was undertaken to determine the effects of catecholamines, agonists, and antagonists of beta-adrenergic receptors (AR) in the LNCaP cell line. Changes in cellular cyclic adenosine-3',5'-monophosphate (cAMP) levels were quantified by the use of a 6 cAMP response element (CRE)-luciferase reporter gene assay. LNCaP cells were transiently transfected with this gene construct, incubated in 96-well microtiter plates for 24 hr, and then treated with beta-AR agonists and/or antagonists for 4 hr. The rank order of potency for catecholamines and known beta-AR agonists was terbutaline(3.31 nM)>isoproterenol(8.31 nM)> or =fenoterol(15 nM)=epinephrine(16.2 nM)>norepinephrine(77.5 nM)>BRL-37344 [(R(*),R(*))-(+/-)4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxy acetic acid, sodium salt] (1000 nM)>dobutamine(1770 nM)>CGP12177 (4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazole-2-one hydrochloride) (inactive). The non-selective beta(1)-/-beta(2)-AR antagonists; propranolol and CGP 12177, at 10(-7)M, inhibited luciferase activity induced by these agonists by 80-96%. Propranolol blocked isoproterenol-induced luciferase responses in a competitive manner (K(B)=1.4 nM). In addition, isoproterenol-activated luciferase expression was blocked more potently by ICI 118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethy) amino]-2-butanol], a beta(2)-AR antagonist than by ICI 89,406 [(+/-)-N-[2-[3-(2-cyanophenoxy-)]-2-hydroxypropylamino]ethyl-N-phenylurea], a beta(1)-AR antagonist, giving K(B) values of 1.07 and 161nM, respectively. These results suggest that the beta(2)-AR is the major subtype mediating catecholamine-induced cAMP changes in LNCaP cells.
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PMID:Evaluation of beta-adrenergic receptor subtypes in the human prostate cancer cell line-LNCaP. 1273 61


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