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Biomedical subjects

D W Snyder

Publications and source records attributed to D W Snyder.

At least 37 records · Page 2Linked to original sources
PubMed1991

Relative potencies of 5-lipoxygenase inhibitors on antigen-induced contractions of guinea pig tracheal strips.

A quantitative method to assess relative potencies (IC50) of 5-lipoxygenase (5-LO) enzyme inhibitors was established in antigen-induced contractions of tracheas isolated from actively sensitized guinea pigs (Schultz-Dale model). The relative potencies of four purported 5-LO inhibitors determined in this tissue assay were compared with those from a crude enzyme preparation isolated from guinea pig neutrophils. All compounds suppressed ovalbumin (OA)-induced tracheal contractions in a concentration-related manner in the presence of indomethacin and pyrilamine. IC50 Values, determined from the percent inhibition values obtained from responses at 30 ng/mL OA of these compounds ranged from 0.56-15 microM. A similar rank order of potency for inhibition of 5-HETE formation from a crude enzyme preparation was observed. This suggested that these agents had a common mechanism of action in the two assay systems and further validated the IC50 values determined in trachea assay. LY171883, an LTD4/LTE4 receptor antagonist, also suppressed OA-induced contractions concentration dependently with an IC50 of 4.9 microM determined by this method. LTD4 concentration-response curves were not altered by any of the four 5-LO inhibitors, ruling out the possibility that these agents were acting as LT receptor antagonists. Results of this study demonstrated that relative potencies of 5-LO inhibitors can be quantitatively assessed using this airway tissue model, which helps in identifying potential therapeutic agents for asthma.

Acetophenones↗
PubMed1990

Pharmacologic characterization of the contractile activity of peptide leukotrienes in guinea-pig pulmonary artery.

The actions of the peptide leukotrienes (LT) LTC4, LTD4 and LTE4 and phenylephrine (PE) were studied in isolated left branches of the guinea-pig pulmonary artery (GPPA). Indomethacin 5 x 10(-6) M enhanced both the potency and maximal response of all agonists, but the effect on LTD4 and LTE4 was larger. The influence of indomethacin suggests the release of an endogenous vasodilating cyclooxygenase product in GPPA. In the presence of indomethacin the rank-order of potency was LTC4 greater than LTD4 greater than LTE4 greater than or equal to PE with respective pD2 values of 7.65, 7.39, 6.35 and 6.26. All further studies were carried out in the presence of 5 x 10(-6) M indomethacin. Removal of the endothelium further increased both potency (greater than 3-fold) and the maximal response of all agonists tested, indicating that a non-cyclooxygenase endothelium-dependent relaxing factor may be present in GPPA. In separate studies, GPPA was demonstrated capable of metabolizing 3H-LTC4 to 3H-LTD4 by an L-serine borate inhibitable gamma-glutamyl transpeptidase. In contrast, relatively little formation of 3H-LTE4 was apparent either from 3H-LTC4 or 3H-LTD4. The LTD4-selective antagonists, LY 171,883 and ICI 198,615 had -log molar KB values of 6.07 +/- 0.14 and 9.38 +/- 0.32, respectively, against LTD4 in the absence of endothelium. The ability of LY 171,883 to antagonize LTC4 was eliminated in the presence of 45 mM serine borate in endothelium denuded tissues. LT receptors in GPPA appear to be heterogeneous and similar to guinea pig airway receptors.

Acetophenones↗
PubMed1990

Evolution of a series of peptidoleukotriene antagonists: synthesis and structure-activity relationships of 1,6-disubstituted indoles and indazoles.

A perception of structural similarities between two independent series of leukotriene antagonists (one emanating from FPL 55712 and one based upon the leukotrienes themselves) led to the discovery of a novel class of indole and indazole derived antagonists of peptidoleukotrienes. A systematic exploration of C-6 substituted 4-(indol-1-ylmethyl)-3-methoxybenzoic acids identified cyclopentylacetamide and cyclopentylurethane as preferred substituents. The corresponding indazoles were equipotent. These compounds are selective leukotriene antagonists with pKB values of 7.5-7.8 vs LTE4 on guinea pig trachea.

Animals↗
PubMed1990

Evolution of a series of peptidoleukotriene antagonists: synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles.

1,3,5-Substituted indoles and indazoles have been studied as receptor antagonists of the peptidoleukotrienes. The best of these compounds generally had a methyl group at the N1 position, a [(cyclopentyloxy)carbonyl]amino or 2-cyclopentylacetamido or N'-cyclopentylureido group at the C-5 position, and an arylsulfonyl amide group as part of the acidic chain at the C-3 position of the ring. Such compounds had in vitro dissociation constants (KB) in the range 10(-9) - 10(-11) M on guinea pig trachea against LTE4 as agonist and inhibition constants (Ki) less than or equal to 10(-9) M on guinea pig parenchymal membranes against [3H]LTD4. A number of compounds were orally effective at doses less than or equal to 1 mg/kg in blocking LTD4-induced "dyspnea" in guinea pigs. Compound 45 [N-[4-[[5-[[(cyclopentyloxy)carbonyl]-amino]-1-methylindol-3- yl]methyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide, ICI 204,219; pKB = 9.67 +/- 0.13, Ki = 0.3 +/- 0.03 nM, po ED50 = 0.3 mg/kg] is currently under clinical investigation for asthma. In the indole series, certain alkylsulfonyl amides possessing a 3-cyanobenzyl substituent at the N-1 position (60, 61) were produced that had KB less than or equal to 10(-9) M on guinea pig trachea.

Animals↗
PubMed1990

A novel series of selective leukotriene antagonists: exploration and optimization of the acidic region in 1,6-disubstituted indoles and indazoles.

A systematic structure-activity exploration of the carboxylic acid region in a series of indole- or indazole-derived leukotriene antagonists 1 led to several discoveries. Use of the 3-methoxy-p-tolyl fragment (illustrated in acid 1) for connecting the indole and the acidic site provides the most potent carboxylic acids 1, tetrazoles 20, and aryl sulfonimides 21. The aryl sulfonimides are 5-500 times more potent (in vitro and/or in vivo) than the corresponding carboxylic acids 1. The o-tolyl sulfonimides such as 114 show greater oral potency than the phenyl sulfonimides at a given level of in vitro activity. Acidic keto sulfone derivatives 10 (Nu = CH-(CO2CH3)SO2Ph) mimic the activity of the sulfonimides.

Animals↗
PubMed1990

Synthesis and in vitro LTD4 antagonist activity of bicyclic and monocyclic cyclopentylurethane and cyclopentylacetamide N-arylsulfonyl amides.

The dissociation constants (KB) at the LTD4 receptor on guinea pig trachea of a series of monocyclic and bicyclic cyclopentylurethane and cyclopentylacetamide N-arylsulfonyl amides have been measured. The KB was found to be remarkably tolerant of changes in the electronic constitution and lipophilicity of the bicyclic ring system (template). Thus, N-[4[[6-[[(cyclopentyloxy)carbonyl]amino]benzimidazol-1- yl]methyl]-3-methoxybenzoyl]benzenesulfonamide (11a) and N-[4-[[5-[[(cyclopentyloxy)carbonyl]amino]benzo[b]thien-3- yl]methyl]-3-methoxybenzoyl]benzene-sulfonamide (25a) had closely similar affinities (pKB, 9.20 and 9.31, respectively; LTE4 as agonist). It has been shown that the hetero-ring of the template need not be aromatic in order to achieve high affinity, since indoline 31 and 2,3-dihydrobenz-1,4-oxazines 37a-c had pKBs greater than 9. Further, it has been shown that an o-aminophenone (see 42 and Figure 3) can function as a template; the template in 42 [see iii] is bicyclic by virtue of the presence of an intramolecular hydrogen bond. In contrast, when the template is a phenyl ring (48), receptor affinity is markedly reduced. These findings support the notion that central bicyclic ring system in this family of peptidoleukotriene antagonists is a molecular feature which helps to preorganize the acylamino and acidic chains and thereby facilitate the molecular recognition event.

Animals↗
PubMed1990

The preclinical pharmacology of ICI 204,219. A peptide leukotriene antagonist.

ICI 204,219 (4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmethy l)-3- methoxy-N-o-tolylsulfonylbenzamide) was designed as a peptide leukotriene (LT) antagonist. The compound is a competitive antagonist of LTD4- and LTE4-induced contraction of guinea pig lung tracheal and parenchymal strips with an apparent negative log molar dissociation constant (KB) of approximately 9.6. ICI 204,219 did not antagonize LTC4-induced contractions of guinea pig trachea when the metabolism of LTC4 to LTD4 and, subsequently, to LTE4 was inhibited. The compound inhibited the binding of [3H]LTD4, [3H]LTE4, and [3H]ICI 198,615 (a potent LT antagonist from a different heterocyclic series) to guinea pig lung parenchymal membranes in a competitive manner, and also inhibited [3H]ICI 198,615 binding to human lung parenchymal membranes. ICI 204,219 did not bind to a variety of other receptors when evaluated at concentrations 1,000- to 10,000-fold higher than the apparent KB value for peptide LT receptors. When administered orally, intravenously, or by aerosol, the compound provided dose-related antagonism of the airway effects of aerosol LTD4 in conscious guinea pigs. ED50 values and pharmacodynamic t1/2 (min) for oral, intravenous and aerosol routes of administration were, respectively: 0.52 mumol/kg, greater than 816 min; 0.046 mumol/kg, 85 min; 5.1 x 10(-6) M, 109 min. ICI 204,219 also produced dose-related inhibition of the effects of LTC4 (aerosol or intravenous administration) on pulmonary mechanics in anesthetized guinea pigs when administered orally, intraduodenally, intravenously, or by aerosol. The compound also reversed bronchospasm produced by LTs. Aerosol ovalbumin antigen-induced bronchospasm in guinea pigs was both inhibited and reversed by ICI 204,219. Lastly, the compound inhibited LTD4-induced increases in cutaneous vascular permeability in guinea pigs, being 1,006- and 679-fold more potent than the first generation LT antagonists LY 171,883 and FPL 55712, respectively. ICI 204,219 is a potent, selective, orally active LT antagonist currently undergoing clinical trials.

Airway Resistance↗
PubMed1989

Class IB antiarrhythmic drugs: tocainide, mexiletine, and moricizine.

Tocainide, mexiletine and moricizine belong to class IB of Vaughan Williams system of classification of antiarrhythmic drugs. Mexiletine and tocainide have little or no effect on Phase 0 of action potential and conduction velocity. Their principal effect is to shorten the action potential duration. Moricizine does not fit precisely into the Vaughan Williams system of classification, but has been categorized with class IB agents because in vitro its effects are similar to those of lidocaine. In this article, the pharmacokinetics, electrophysiologic effects, and clinical uses of these three agents are reviewed.

Anti-Arrhythmia Agents↗
PubMed1988

U19052 (ICIAm): a novel leukotriene analog which antagonizes LTC4, LTD4, and LTE4.

Chemically stable analogs of peptide leukotrienes (LT) have been developed in our laboratories by replacement of the natural triene backbone with a C7H15 substituted aromatic moiety (1). These analogs are potent agonists of airway smooth muscle. Substitution in the peptide region resulted in U19052, an LT receptor antagonist. U19052 antagonized LT-induced contractions of guinea-pig tracheal spirals in a concentration-related manner. The pA2 values versus LTD4 and LTE4 were 6.0 and 5.7, respectively, with slopes which were not significantly different from unity. LTC4-induced contractions were antagonized by U19052 with a pKB of 5.6 obtained either in the absence or presence of L-serine borate. In contrast, carbachol and histamine concentration-response curves were not altered by U19052. LTD4 or LTE4 contractions of isolated guinea-pig ileum were antagonized by U19052 with pKB values of 7.2. The results indicate that potent selective LT antagonists can be developed from stable analogs of leukotrienes. U19052, an example of this series, appears to be as effective in antagonizing LTC4- as well as LD4- and LTE4-induced contractions in guinea-pig tracheal spirals.

Animals↗
PubMed1988

Conscious guinea-pig aerosol model for evaluation of peptide leukotriene antagonists.

A new conscious animal model for evaluating leukotriene antagonists is described. The model consists of monitoring the change in the respiratory pattern induced by aerosol administration of various airway constrictors in six guinea pigs secured in a plexiglass chamber by a neck yoke. The animals are pretreated with indomethacin (10 mg/kg, i.p.) and propranolol (5 mg/kg, i.p.) 30 min prior to the challenge. After a 30-min stabilization period, the animals are challenged by various agonists delivered via a Monaghan ultrasonic nebulizer at a flow rate of 2.0 L/min for 5 min. The end point is defined as the onset of slow, labored abdominal breathing (dyspnea) measured in seconds. Peptide leukotrienes (LTs) (30 nM-60 microM) produced concentration-related decreases in time to dyspnea with a rank order of potency of LTD4 greater than LTC4 greater than LTE4. LTD4 was 1,000-fold more potent than histamine or carbachol. Pretreatment of the animals with either FPL55712 or LY171883 delayed the time to reach dyspnea induced by LTD4. In contrast, pyrilamine, cyproheptadine, and phenoxybenzamine failed to alter LTD4-induced dyspnea. The results indicate that this model is useful in assessing the efficacy of LT receptor antagonists in vivo.

Administration, Inhalation↗
PubMed1988

Left ventricular aneurysm repair with myocardial revascularization: an analysis of 246 consecutive patients over 15 years.

From 1970 to 1985, 246 consecutive patients with left ventricular (LV) aneurysm underwent repair and concomitant myocardial revascularization at Ochsner Foundation Hospital. The overall incidence of perioperative death was 7.3%. Although the deaths were mainly cardiac related (10/18) with congestive heart failure (CHF) as the leading cause (6/10), 8 deaths were of noncardiac origin. Perioperative mortality increased significantly in patients with mitral regurgitation (MR) (22%; p = 0.0008); perioperative mortality for patients without MR was 4.8%. The overall 5-year survival was 69%. Late deaths were caused most commonly by myocardial infarction (20/32) with only 7 due to CHF. Predictors of long-term survival were related to LV function preoperatively: absence of CHF (p = 0.001); LV end-diastolic pressure less than or equal to 20 mm Hg (p = 0.03); and ejection fraction greater than or equal to 35% (p = 0.02). Factors that did not significantly affect long-term survival were type of aneurysm repair (resection or plication), morphology of left anterior descending coronary artery (occlusion or stenosis), and size of the aneurysm.

Adult↗
PubMed1988

Synthesis and pharmacological characterization of a series of leukotriene analogues with antagonist and agonist activities.

The synthesis and biological characterization of a series of novel leukotriene antagonists and agonists are reported. All of these compounds are derivatives of (5S,6R,7Z)-5-hydroxy-6-mercapto-9-phenyl-7-nonenoic acid. One of the more potent compounds is (5S,6R,7Z)-6-[[(4-carboxy-2-methoxyphenyl)methyl]thio]-5-hydroxy-9 -(4- heptylphenyl)-7-nonenoic acid (3f). In vitro evaluation of this compound on guinea pig trachea revealed that it is a competitive antagonist of LTD4 and LTE4 with pKB values of 6.4 and 5.8, respectively. On guinea pig ileum, the pKB values obtained for it with LTD4 and E4 were both 7.2. The selectivity of 3f was shown by its lack of effect on carbachol, histamine, and barium chloride concentration-response curves in guinea pig trachea.

Animals↗
PubMed1987

Pharmacologic profile of chemically stable analogs of peptide leukotrienes.

Peptide leukotrienes are potent constrictors of airway smooth muscle but lack chemical stability. Replacement of the natural triene backbone of leukotrienes with 9-(x-heptylphenyl)-7-nonenoic acid (x = 2, 3, or 4) renders these analogs chemically stable and pharmacologically active. The para, meta and ortho substitutions of the heptyl (C7H15) moiety were combined with the different leukotriene peptide substitutions of glutathionyl, C-peptide of leukotriene C4, cysteinylglycinyl, D-peptide of leukotriene D4, and cysteinyl, E-peptide of leukotriene E4 rendering nine active analogs. The pharmacology of these analogs was evaluated in isolated guinea-pig tracheal strips. The para-substituted C-peptide analog was the most potent; however, it was 100-fold less potent than leukotriene C4. The contractile activities of the para- and meta-substituted C-peptide analogs were enhanced by L-serine borate (45 mM), indicating they were substrates for gamma-glutamyl transpeptidase. FPL55712 (10 microM) failed to antagonize the substituted C-peptide analogs independent of the presence of L-serine borate. The contractile activities of the three substituted D-peptide analogs were enhanced by L-cysteine, indicating they are all substrates for aminopeptidase. The para-substituted D-peptide analog was the most potent D-peptide analog, but it was 10- and 1,000-fold less active than the para-substituted C-peptide analog and leukotriene D4, respectively. The para- and meta-substituted E-peptide analogs were approximately 1,000-fold less potent than leukotriene E4, and like the substituted D-peptide analogs, they were antagonized by FPL55712. In contrast, the ortho-substituted E-peptide analog was devoid of intrinsic activity but antagonized leukotriene E4-induced contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Overweight and sudden death. Increased ventricular ectopy in cardiopathy of obesity.

Obesity has been documented to be an independent risk factor for sudden death and other cardiovascular mortality. The present study was designed to monitor and quantify cardiac arrhythmias in obese subjects with and without eccentric left ventricular hypertrophy, who were matched with regard to arterial pressure, age, sex, and height with lean subjects. Prevalence of premature ventricular (but not atrial) contractions was 30 times higher in obese patients with eccentric left ventricular hypertrophy compared with lean subjects. Similarly, obese patients with left ventricular hypertrophy scored higher with regard to the classification of Lown and Wolf than those without left ventricular hypertrophy and lean subjects having the same level of arterial pressure. Patients' class in the Lown and Wolf system correlated with ventricular diastolic diameter and left ventricular mass. Thus, heart enlargement of the eccentric type as a consequence of obesity predisposes to excessive ventricular ectopy. Echocardiographic assessment and electrocardiographic monitoring allow us to identify the patients who are at highest risk of more serious arrhythmias or possibly sudden death and to subject them to the most specific preventive and therapeutic measures.

Adult↗
PubMed1987

In vitro pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist.

ICI 198,615 is a representative compound from a new class of peptide leukotriene (LT) receptor antagonists. In isolated guinea pig trachea and parenchymal lung strips, ICI 198,615 demonstrated competitive antagonism of the contractile activity of LTD4 and LTE4 with pA2 values of 10.1 to 9.5, respectively. The compound also appeared to antagonize the contractile activity of LTC4 in guinea pig trachea; however, in the presence of an inhibitor of the metabolism of LTC4 to LTD4, ICI 198, 615 provided a pKB value of 5.3, indicating weak antagonism at the LTC4 receptor. ICI 198,615 was also a potent antagonist of LTC4 and LTD4 in isolated human bronchi and pulmonary veins with pKa values of 9.75 +/- 0.32 to 9.20 +/- 0.24, respectively. When evaluated for activity on a broad variety of non-LT receptors, the compound displayed a minimal selectivity of 6310 and a maximal selectivity of greater than 125,000 for the LTE4 receptor. These in vitro studies indicate that ICI 198,615 is the most potent and selective peptide LT receptor antagonist described to date.

Acetophenones↗
PubMed1987

In vivo pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist.

The in vivo pharmacology of ICI 198,615, a highly potent and selective peptide leukotriene (LT) receptor antagonist, is described. In a conscious guinea pig model, ICI 198,615 provided dose-related antagonism of aerosol LTD4-induced dyspnea when administered p.o., i.v. or by aerosol. The pharmacologic half-lives of ICI 198,615 by these routes of administration were greater than 16 hr, 68 min and 34 min, respectively. In pulmonary mechanics studies in which the effects of i.v. or aerosol administration of LTC4 and LTD4 on pulmonary resistance (Rp) or dynamic lung compliance (Cdyn) could be quantitated, ICI 198,615 provided dose-related antagonism when administered p.o., i.d, i.v. or by aerosol. The compound also antagonized LTE4-induced changes in Rp and Cdyn when administered i.v. ICI 198,615 reversed the effect of LTC4, LTD4 and LTE4 on Rp, as well as the effect of LTC4 and LTE4 on Cdyn. The compound was less able to reverse the effect of LTD4 on Cdyn. These results indicate that ICI 198,615 possesses an in vivo profile which is consonant with utility in the treatment of allergic diseases.

Aerosols↗
PubMed1986

Postnatal developmental changes of tryptophan hydroxylase activity in serotonergic cell bodies and terminals of rat brain.

Tryptophan hydroxylase (TPH) is the rate limiting enzyme in serotonin biosynthesis, so its development is very important to the functional maturation of the serotonergic neurons. In the present study, we examined changes of TPH activity in serotonergic cell bodies and terminals of rat brain during postnatal development. TPH activity reached its peak in the cell body regions at 24 days after birth, while the enzyme activity in a terminal region rose to its plateau at day 30. TPH activity in adult rat is the highest in nucleus raphe dorsalis, then nucleus raphe centralis and hypothalamus in a decreasing order.

Animals↗