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.

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.

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.

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 β-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.

AbstractAusgehend von dem Epoxid (I) oder dem Alkohol (IV) werden die Aminoalkohole (II) synthetisiert, von denen die meisten eine hohe Bindun saffinität zu zidrener en β‐Reze toren besitzen.

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.

MK‐801 at doses < 100 μg/kg given orally induced an ipsilaterally directed directed rotational response in rats with a unilateral nigrostriatal lesion produced by 6‐hydroxydopamine. (+)‐Amphetamine, amfonelic acid, and methylphenidate also evoked ipsilateral turning with their dose‐response lines lying considerably to the right of that for MK‐801. Rotations caused by a standard test dose of 50 μg/kg of MK‐801 were reduced by pretreatment with haloperidol (ED50 = 0.068 mg/kg IP), clozapine (ED50 = 3.35 mg/kg IP), or prazosin (ED50 = 0.15 mg/kg SC). MK‐801‐induced turning was also inhibited by pretreatment with α‐methyl‐p‐tyrosine (α‐MPT) and blocked by reserpine.

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.

The benzodiazepine anxiolytics flurazepam and diazepam and CL 218872, zopiclone and two β-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.

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.

Taurine, a weak β-adrenergic agonist in rat pineal cultures, causes a 32% increase in the binding of the β-adrenergic antagonist 3H-dihydroalprenolol to rat brain membranes at a concentration of 100 mM. No significant effect was seen at 10 mM however. The amino acid is also effective in displacing 3H-diazepam (Ki, 32.8 mM) and 3H-muscimol (Ki, 32.4 μM), ligands for the benzodiazephine and GABA receptor, respectively. β-Alanine, a taurine analog, is more effective in displacing 3H-diazepam (Ki, 13.8 mM) and 3H-muscimol (Ki, 9 μM) but shows no significant enhancement of 3H-dihydroalprenolol binding. While endogenous taurine levels in brain are in the millimolar range, the physiological significance of these observations remains to be determined.

AbstractDer Thioether (I) ergibt bei der Oxidation das Sulfoxid (II) sowie die Sulfone (III) und (IV), von denen (III) durch eine Grignard‐Reaktion mit nachfolgender Dehydratisierung in das Piperidinderivat (VII) umgewandelt wird.

These experiments examined the potency of choline as a cholinergic agonist at both muscarinic and nicotinic receptors in rat brain and peripheral tissues. Choline stimulated the contraction of isolated smooth muscle preparations of the stomach fundus, urinary bladder and trachea and reduced the frequency of spontaneous contractions of the right atrium at high micromolar and low millimolar concentrations. The potency of choline to elicit a biological response varied markedly among these tissues; ec50 values ranged between 0.41 mM in the fundus to 14.45 mM in the atrium. Choline also displaced [3H]quinuclidinyl benzilate binding in a concentration-dependent manner although, again, its potency varied among different brain regions (Ki = 1.2 to 3.5 mM) and peripheral tissues (Ki = 0.28 to 3.00 (mM). Choline exhibited a comparable affinity for nicotinic receptors. It stimulated catecholamine release from the vascularly perfused adrenal gland (ec50 = 1.3 mM) and displaced l-[3H]nicotine binding to membrane preparations of brain and peripheral tissues (Ki = 0.38 to 1.17mM). However, the concentration of choline required to bind to cholinergic receptors in most tissues was considerably higher than serum levels either in controls (8–13 μM) or following the administration of choline chloride (200 μM). These results clearly demonstrate that choline is a weak cholinergic agonist. Its potency is too low to account for the central nervous system effects produced by choline administration, although the direct activation of cholinergic receptors in several peripheral tissues may explain some of its side effects.

Abstract— The binding of [3H]muscimol, a potent GABA agonist, to crude synaptic membranes prepared from rat brain was studied using a filtration method to isolate membrane‐bound ligand. Specific binding was found to be saturable and occurred to two binding sites of Kd5 5 and 30 nm. Binding was Na+‐independent and enhanced by both freezing and Triton treatment. Regional and subcellular distribution studies and pharmacological characterization of specific [3H]muscimol binding are consistent with binding to the synaptic GABA receptor.

5-(2,4-Difluorophenyl)salicylic acid, diflunisal (25), is the best compound, in terms of both efficacy and safety, from over 500 salicylates investigated in our laboratories. It is a chemically distinct, nonacetylating salicylic acid, more active than aspirin as an analgesic and antiinflammatory agent and superior in duration of action and therapeutic index. Some recent clinical and biochemical observations are briefly discussed.

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.

British Journal of Clinical PharmacologyVolume 4, Issue S1 p. 19S-29S Free Access Pharmacology and toxicology of diflunisal. CA Stone, CA StoneSearch for more papers by this authorCG Van Arman, CG Van ArmanSearch for more papers by this authorVJ Lotti, VJ LottiSearch for more papers by this authorDH Minsker, DH MinskerSearch for more papers by this authorEA Risley, EA RisleySearch for more papers by this authorWJ Bagdon, WJ BagdonSearch for more papers by this authorDL Bokelman, DL BokelmanSearch for more papers by this authorRD Jensen, RD JensenSearch for more papers by this authorB Mendlowski, B MendlowskiSearch for more papers by this authorCL Tate, CL TateSearch for more papers by this authorHM Peck, HM PeckSearch for more papers by this authorRE Zwickley, RE ZwickleySearch for more papers by this authorSE McKinney, SE McKinneySearch for more papers by this author CA Stone, CA StoneSearch for more papers by this authorCG Van Arman, CG Van ArmanSearch for more papers by this authorVJ Lotti, VJ LottiSearch for more papers by this authorDH Minsker, DH MinskerSearch for more papers by this authorEA Risley, EA RisleySearch for more papers by this authorWJ Bagdon, WJ BagdonSearch for more papers by this authorDL Bokelman, DL BokelmanSearch for more papers by this authorRD Jensen, RD JensenSearch for more papers by this authorB Mendlowski, B MendlowskiSearch for more papers by this authorCL Tate, CL TateSearch for more papers by this authorHM Peck, HM PeckSearch for more papers by this authorRE Zwickley, RE ZwickleySearch for more papers by this authorSE McKinney, SE McKinneySearch for more papers by this author First published: February 1977 https://doi.org/10.1111/j.1365-2125.1977.tb04510.xCitations: 58AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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ZWICKEY, R.E., PECK, H.M., BAGDON, W.J., BOKELMAN, D.L., BROWN, W.R., HITE, M., JENSEN, R.D., MATTIS, P.A., MENDLOWSKI, R., PORTER, C.C., TATE, C.L. & STONE, C.A. (1974). Preclinical toxicological studies of carbidopa and combinations of carbidopa and levodopa. Toxic, appl. Pharmac. 29, 181– 195. Citing Literature Volume4, IssueS1February 1977Pages 19S-29S ReferencesRelatedInformation