Gastric antisecretory and pharmacologic properties of N,N-dimethyl-N'-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyridyl)ur ea (L-634,366).

N,N-Dimethyl-N'-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyridyl)urea (L-634,366) was selected from a series of pyridylurea compounds with antisecretory activity as a potential therapeutic agent for the treatment of ulcer disease. L-634,366 was an effective inhibitor of gastric secretion evoked by gastrin, histamine and 2-desoxy-D-glucose (2-DG) in conscious dogs. Orally, L-634,366 was slightly less potent than the reference H2 receptor blocker, cimetidine as an inhibitor of secretion evoked by histamine, but was equipotent as an inhibitor of secretion evoked by gastrin and 2-DG. In vitro L-634,366 was a weak antagonist of histamine (H2) receptor responses in the guinea-pig atria and rat uterus; in the atria the antagonism appeared to be noncompetitive. In the anesthetized dog, L-634,366 possessed weak anticholinergic activity as compared to atropine in reducing vagally mediated cardiovascular, antral motor responses and with regard to antagonizing the pressor response to the muscarinic stimulant, McN 343-A. The anticholinergic activity of L-634,366 was lower and more selective than that of pirenzepine or atropine in producing mydriasis in mice, in antagonizing acetylcholine induced bradycardia in guinea-pig atria, methacholine and acetylcholine elicited contractions in the guinea-pig ileum and QNB binding to muscarinic receptors. L-634,366, like carbenoxolone, increased incorporation of 3H-glucosamine in gastric mucous indicating an increase in synthesis or turnover of mucous. L-634,366 is a novel compound possessing a broad spectrum of antisecretory activity; in vitro studies suggested a weak noncompetitive inhibition of the histamine-H2 receptor in atria.

A structurally novel stimulator of guanylate cyclase with long-lasting hypotensive activity in the dog.

Studies were undertaken to characterize the activity of diphenyliodonium hexafluorophosphate (DIFP) as a structurally novel stimulator of soluble guanylate cyclase from rat lung and make comparisons to the activity of sodium nitroprusside (SNP). In addition, the effects of these two compounds on several cardiovascular parameters in anesthetized dogs were determined. DIFP stimulated guanylate cyclase activity within the same concentration range (10-300 microM) as SNP, causing a maximal 2-3-fold activation. The activities of both SNP and DIFP were dependent on the presence of dithiothreitol and inhibited by methylene blue. In anesthetized dogs, DIFP (i.v.) elicited a dose-related, long-lasting fall (greater than 3 h) in mean arterial pressure (MAP) which was accompanied by a reduction in total peripheral resistance and a transient rise in cardiac output. These effects on MAP were similar to those of SNP except they were of a much longer duration. In addition, both SNP and DIFP produced slight bradycardia and reduced negative dP/dt. These results suggest that DIFP and SNP, while structurally dissimilar, activate guanylate cyclase by a related mechanism which may be involved in vascular relaxation leading to reduced blood pressure.

Comparison of central gastric antisecretory effects of desmethylimipramine, doxepin and pirenzepine in rats.

Certain tricyclic drugs, some of which are primarily used clinically as antidepressants, have been shown to act as gastric antisecretory agents. The anatomical site(s) and mechanism(s) of action of these agents is, however, in most cases unclear. In this study, we found that desmethylimipramine (DMI) was approximately 28 times more potent in inhibiting gastric acid secretion when administered intracerebroventricularly (i.c.) than when administered intravenously (i.v.) in pylorus-ligated rats, which is indicative of a site of action in the central nervous system. Qualitatively similar results were obtained with pirenzepine where the i.c./i.v. potency ratio was 8. Doxepin also preferentially inhibited acid secretion when given i.c. at low but not at high doses. Atropine and chlorpromazine were equipotent antisecretory agents by both routes of administration. Doxepin and DMI but not pirenzepine were effective inhibitors of brain stem norepinephrine uptake in vitro thus making this an unlikely common mechanism to explain the central actions of these compounds.

Ivermectin interactions with benzodiazepine receptors in rat cortex and cerebellum in vitro.

The anthelmintic macrolide, ivermectin, enhances the binding of benzodiazepine agonist ( [3H]-diazepam) and antagonist ( [3H] beta-carboline ethyl ester) ligands to rat cortical and cerebellar membrane preparations. Enhancement of benzodiazepine agonist binding is partially additive with that of gamma-aminobutyric acid (GABA) and is inhibited by etazolate, bicuculline, and the steroid GABA antagonist R5135. Ivermectin-stimulated benzodiazepine antagonist binding is enhanced by bicuculline and inhibited by GABA and etazolate. The modulatory effects of bicuculline are chloride-dependent. The stimulatory effects of ivermectin, while quantitatively different in cortex and cerebellum, are qualitatively similar in both brain regions and are reduced in the presence of chloride. Ivermectin effects on benzodiazepine ligand binding to the benzodiazepine receptor complex and the differences in the effects of GABA, bicuculline, and R5135 on ivermectin-stimulated agonist and antagonist binding may provide evidence for distinct differences in the recognition sites for the two classes of benzodiazepine receptor ligand and their interactions with other components of the receptor complex.

Synthesis and receptor binding studies relevant to the neuroleptic activities of some 1-methyl-4-piperidylidene-9-substituted-pyrrolo[2,1-b][3]benzazepine derivatives.

The synthesis of a series of 1-methyl-4-(9-substituted-11H-pyrrolo[2,1-b]benzazepin-11-ylidene)piperidines (4a-f) and 1-methyl-4-(9-substituted-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidines (4g-l) is described. As with th e 3-substituted cyproheptadine compounds 1b-e, atropisomerism exists in 4b-f, but unlike the enantiomers of 1b-e, the pyrrolobenzazepine enantiomers racemize at room temperature. Thus, the bromo compound (+)-4b has a half-life of 128 +/- 1 min at 25 degrees C, while the chloro compound (-)-4c has a half-life of 114 +/- 9 min at 25 degrees C. Compounds 4a-l have been examined for receptor binding affinities in assays that have been recognized as predictive for antipsychotic activity. The displacement of specifically bound tritiated ligands, comprising the dopamine antagonist [3H]spiperone, the dopamine agonist [3H]apomorphine, the muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate (QNB), the alpha-adrenergic antagonist [3H]prazosin, the alpha-adrenergic agonist [3H]clonidine, the serotonin-1 binding agent [3H]serotonin, and the mixed serotonin agonist-antagonist [3H]lysergic acid diethylamide (LSD), by 4a-l has been measured utilizing membrane preparations of mammalian brain. Certain of the features of the receptor binding of these compounds have been shown to be common to several of the receptor sites. Data from these binding studies have been compared to corresponding data previously obtained for a series of chiral 3-substituted cyproheptadine analogues, and the receptor binding data of the two classes of compounds are discussed with respect to their molecular geometries.

Antihypertensive beta-adrenergic blocking agents: N-aralkyl analogues of 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine.

An interest in dual-acting antihypertensive agents, specifically those related to (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1), led us to probe the contribution of the side-chain amino substituent in this series. The ability of 1 and its various analogues to displace radiolabeled alpha 1 (WB-4101 and prazosin) and beta (dihydroalprenolol) adrenergic receptor ligands was assessed by receptor-binding techniques. Most of the compounds exhibited high beta-adrenoceptor binding affinities, but only the N-aralkylamino-substituted compounds showed high alpha 1-adrenoceptor affinities. Therefore, the vasodilation shown by 1 was not due to an interaction with the alpha 1 adrenoceptor. The aralkylamino analogues of 1 in spontaneously hypertensive rats and anesthetized dogs exhibited antihypertensive activity and alpha 1-adrenoceptor blocking properties. Unlike the preference shown by beta-adrenoceptors for S enantiomers in this oxymethylene class of beta blockers, the chirality at the secondary hydroxy center made only a minor contribution to the affinity for the alpha 1-adrenoceptor and even less of a contribution to the observed antihypertensive effects. This lack of chiral influence at the hydroxy center confirmed what had been previously observed in more limited studies with the isomers of both labetalol and medroxalol.

Chronic in vivo treatment with desmethylimipramine and mianserin does not alter adenosine A-1 radioligand binding in rat cortex.

Antidepressants and electroconvulsive shock therapy (ECS) have been reported to alter adenosine-sensitive adenylate cyclase responses in rat brain, suggesting an involvement of the purine in the mechanisms by which antidepressants and antidepressant therapy produce their clinical effects. Chronic (14-21 days, 10 mg/kg/day by Alzet minipump) treatment with desmethylimipramine (DMI) and mianserin, while producing changes in beta-adrenoceptor (DMI) and serotonin-2 (DMI and mianserin) radioligand binding similar to those reported in the literature, has no effect on adenosine A-1 radioligand binding.

Interaction of the benzodiazepine antagonists, CGS 8216 and Ro 15-1788, with central adenosine A-1 receptors.

Although the potent benzodiazepine antagonist CGS 8216 has in vitro activity indicative of an interaction with central adenosine systems, neither it, nor the benzodiazepine antagonist Ro 15-1788 showed any great degree of interaction with central adenosine A-1 receptors as measured by radioligand binding. It is concluded that interaction of benzodiazepine antagonists with A-1 receptors is not a property related to their antagonist activity.

Interaction of avermectins with [3H]beta-carboline-3-carboxylate ethyl ester and [3H]diazepam binding sites in rat brain cortical membranes.

The binding of [3H] beta-carboline-3-carboxylate ethyl ester ([3H] beta-CCE), a ligand for the benzodiazepine receptor in the mammalian CNS, to rat cortical membranes, is enhanced by avermectin B1a and its therapeutic formulation, Ivermectin. In contrast to the effects of the avermectins on [3H]diazepam binding, which involve changes in both receptor affinity and number, increases in beta-CCE binding, which are much less than those observed for the benzodiazepine ligand, involve only alterations in receptor number. This Bmax increase is bicuculline insensitive whereas Ivermectin effects on benzodiazepine binding are partially antagonized by GABA antagonist. The data suggest a differential interaction by the avermectins on benzodiazepine and beta-CCE binding sites in rat cortical membranes and indicate that these macrolide anthelmintics may be a useful tool for characterizing benzodiazepine/anxiolytic receptor subtypes.

Interaction of putative anxiolytic agents with central adenosine receptors.

The benzodiazepine anxiolytics flurazepam and diazepam and CL 218872, zopiclone and two beta-carboline ethyl carboxyl esters, compounds which are potent displacers of specific [3H]diazepam binding from rat brain membranes, have little or no activity in displacing [3H]2-chloroadenosine ([3H]2-CADO) from central A1-adenosine receptors. Conversely, the purine agonists, 1-N6-phenylisopropyladenosine, N6-cyclohexyladenosine, 2-chloroadenosine, and the adenosine antagonist 8-phenyltheophylline have no significant effect on [3H]diazepam binding. Etazolate (SQ 20009) and Avermectin B1a which enhance [3H]diazepam binding in vitro were also without significant effect on [3H]2-CADO binding. The lack of correlation of the activities of the compounds examined in the two binding assays is discussed in relation to the hypothesis that purine-like compounds may be involved in the molecular mechanisms related to anxiolytic action at the receptor level.

Biochemical characterization of putative central purinergic receptors by using 2-chloro[3H]adenosine, a stable analog of adenosine.

After pretreatment of rat brain synaptic membranes with adenosine deaminase to remove endogenous adenosine, 2-chloro[3H]adenosine, a stable analog of adenosine, binds to two sites with Kd values of 1.3 and 16 nM and corresponding Bmax values of 207 and 380 fmol/mg of protein. Binding is reversible, and the highest density of sites occurs in enriched synaptosomal fractions. In peripheral tissue, negligible binding is observed in heart, kidney, and liver, while testicle has 11 fmol of binding sites/mg of protein. In brain, caudate and hippocampus have the highest density of sites, and spinal cord and hypothalamus have the lowest. This high-affinity binding is stereospecific; the L diasteromer of N6-phenylisopropyladenosine is approximately 30-times more potent as a displacer of 2-chloro[3H]adenosine than the D isomer and is also sensitive to theophylline (IC50 = 8.8 microM) and other purine-related compounds. Several putative neurotransmitters, neurotransmitter antagonists, and other centrally active compounds have no effect on binding. The data are consistent with the hypothesis that 2-chloro[3H]adenosine is binding to central purinergic receptors.

2-(Substituted phenyl)oxazolo[4,5-b]pyridines and 2-(substituted phenyl)oxazolo[5,4-b]pyridines as nonacidic antiinflammatory agents.

Some 2-(substituted phenyl)oxazolo[4,5-b]pyridines and 2-(substituted phenyl)oxazolo[5,4-b]pyridines have good antiinflammatory and analgesic activity. A few possess activity comparable to phenylbutazone or indomethacin without producing the irritation in the gastrointestinal tract that acidic antiinflammatory compounds cause.

Criterion-referenced testing in medical technology education: Professional Performance Situation Model.

In applying the Professional Performance Situation Model to the medical technology profession, situations describing actual laboratory performance are used as a basis for defining competence. As these definitions of competence are derived, appropriate criterion-referenced (domain-referenced) assessments are designed to measure the achievement of competence. This paper describes the process by which situations representing clinical practice are derived, the extrapolation of skill and knowledge statements reflecting expected performance, the generation of domains of competence, the design of criterion-referenced assessments, and some examples of prototype instruments used to assess attainment of the competence. The techniques include multiple choice items, checklists for use in the clinical component of the educational experience, and the adaptation of the written simulation for instruction and evaluation in medical laboratory sciences education. Validity of this approach is discussed, as well as possible implications for its use in developing assessments to measure continued competence in the profession beyond the baccalaureate education.

Identification of the biologically active form of sulindac.

In five animal species, the only quantitatively significant biotransformations undergone by cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl) benzylidene]indene-3-acetic acid (sulindac) are oxidation of its sulfinyl substituent to sulfone, and reduction to sulfide. The former metabolite is eliminated unchanged and elicits no pharmacological response. The sulfide, on the other hand, is readily reoxidized in vivo to sulindac. In each of seven in vivo models of inflammation, sulfide administered as such is more active than sulindac. The inference that the activity of sulindac might be attributed in whole or in part to the sulfide was tested directly by comparison of responses with concentrations of each reduction oxidation species in appropriate biological fluids. Regression analyses of circulation levels of sunlindac and sulfide vs. inhibition of rat paw edema, and of their levels in synovial fluid vs. response in the dog knee joint assay, show highly significant correlations only for sulfide. Sulindac thus appears to be a "latentiated" or "pro-drug," oral dosage with chich may circumvent the gastrointestinal side effects commonly associated with nonsteriod anti-inflammatory agents.