Effect of Receiver Fluid pH on in Vitro Skin Flux of Weakly lonizable Drugs

In in vitro skin permeation experiments, the pH of viable epidermis is readily conditioned by the receiver fluid. For weakly ionizable compounds, the flux determined experimentally thus depends on the receiver fluid pH. The purpose of the present work is to characterize this pH effect, since nonphysiological conditions have often been used in the receiver fluid to enhance the solubility of the subject compounds. A transport model was developed to analyze the above-mentioned pH effect of the receiver fluid on the steady state flux of weakly ionizable drugs. The results showed that the skin flux had a strong dependence on pH for those compounds with high intrinsic partition coefficients. Experimentally, this pH effect was observed with a model acid and a model base. The skin flux was found to have a profound dependence on the receiver fluid pH. This dependence also correlates with the octanol/water partition coefficient of the molecule. It was concluded that the use of a physiological receiver fluid would be crucial for a realistic estimation of transdermal potential. The results also suggested that, for weakly ionizable compounds with high partition coefficients, the viable epidermis could be a significant transport barrier for systemic absorption.     

In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species

The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP(+)-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structure-toxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP(+)-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.     

Evaluation of PMF scoring in docking weak ligands to the FK506 binding protein.

A new knowledge-based scoring function (PMF-score), implemented into the DOCK4 program, was used to screen a database of 3247 small molecules for binding to the FK506 binding protein (FKBP). The computational ranking of these compounds was compared to the binding affinities measured by NMR. It was demonstrated that small, weakly binding molecules have, on average, higher computational scores than nonbinders and are enriched in the upper ranks of the computational scoring lists. In addition, the results obtained with the PMF scoring function were superior (by 30-120% larger enrichment factors) to those obtained with the standard force field score of DOCK4. The reliable ranking of small, weakly binding molecules offers new ways of designing building blocks in combinatorial libraries as well as SAR by NMR libraries with the increased chance of identifying suitable lead compounds for drug design.     

Antiinflammatory activity of N-(2-benzoylphenyl)alanine derivatives

A series of N-(2-benzoylphenyl)alanine derivatives were synthesized and tested for antiinflammatory activity in the Evans blue-carrageenan induced pleural effusion assay. The target compounds were envisioned to bind to a receptor site on the cyclooxygenase enzyme by a mechanism first proposed by Appleton and Brown. Of the 21 compounds prepared, two were found to be one-tenth as potent as indomethacin in the pleurisy model and one compound was tested and found to be weakly active in the adjuvant arthritis model.     

Effects of tricyclic antidepressant drugs on energy-linked reactions in mitochondria

The effects of impramine and chlorimipramine on energy-linked reactions in mitochondria were characterized. Both compounds exhibited some characteristics of classical uncouplers of oxidative phosphorylation, i.e. they released respiratory control, hindered ATP synthesis, and enhanced ATPase activity of isolated rat liver mitochondria. Unlike classical uncouplers, however, these compounds only weakly stimulated proton uptake in intact mitochondria. They also exhibited unusual effects on energy-linked reactions in beef heart submitochondrial particles (SMP). Both compounds inhibited NADH oxidation in SMP in an "oligomycin-like" manner, and inhibited ATPase activity of SMP and the soluble F1-ATPase. In contrast, the drugs weakly inhibited ATPase activities of bovine adrenal gland chromaffin granules and resealed granule ghosts. The mechanisms responsible for the multiple effects on mitochondrial energy-linked processes are unclear. They may be related to the hydrophobicity of the drugs, as has been shown for other hydrophobic amines.     

Synthesis and antimycobacterial activity of carbamate derivatives of 1,2-oxazine

Aseries of carbamate derivatives of 1,2-oxazine was obtained by means of [2 + 4]-cycloaddition of 1,3-dienes to C-nitroso-alkyl-N-arylcarbamates. The antimycobacterial activity of the synthesized compounds with respect to Mycobacterium tuberculosis and Mycobacterium lufu species was studied in vitro in comparison to isoniazid and dapsone. The activity of the newly synthesized compounds significantly depends on the nature and position of substituents in the oxazine nucleus and weakly depends on the nature of substituents in the carbamate moiety. Among the compounds tested, the maximum antimycobacterial activity was observed for 4,5-dimethyl-2-(p-methoxycarbonylamino)phenyl-3,6-dihydro-1,2-oxazine. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 7, pp. 32–34, July, 2006.     

Determination of iodide in metabolic studies of 125I-labeled compounds.

Methods capable of measuring inorganic iodide in the presence of other highly polar metabolites were developed in support of studies concerning the metabolism of 125I-labeled compounds. The methods included separation of iodine on a weakly basic resin paper followed by gamma-counting, methyl iodide exchange, and reverse isotopic dilution.     

Study of artificial flavouring substances for mutagenicity in the salmonella/microsome, Basc and micronucleus tests

Seventy-six compounds used as artificial flavouring substances in food products were studied for mutagenic properties by the use of the Salmonella/mammalian microsome test (Ames test), Basc test on Drosophila melanogaster and micronucleus test on mouse bone marrow. The following four compounds were mutagenic in Ames tests: ethyl nitrite, ethyl 3-phenylglycidate, 6-methylquinoline and musk ambrette. Of these, ethyl nitrite and musk ambrette also induced a significant (P 0.01) increase in sex-linked recessive lethal mutations in Drosophila. Two further compounds, ethyl 3-methyl-3-phenylglycidate and 4-n-propylanisole, appeared weakly mutagenic in Drosophila only. The result with 4-n-propylanisole was judged to be of equivocal biological significance. None of the flavouring substances induced micronuclei, i.e. cytogenetic damage in the bone marrow of mice.     

Renal tubular transport of paracetamol and its conjugates in the dog.

1 The renal tubular transport of paracetamol and its conjugates was investigated with renal clearance and stop flow studies in the dog. Paracetamol is sparingly bound to plasma proteins and therefore undergoes glomerular filtration. It is reabosrbed in the renal tubules by simple diffusion. 2 The conjugates of paracetamol, the sulphate and the glucuronide, both undergo glomerular filtration being weakly protein bound. At low concentrations in plasma both compounds are secreted by an active transport process. At higher concentrations both compounds are reabsorbed. Clearances are not dependent on urinary pH or flow rate. It is concluded that reabsorption is not a passive process but that there is an active bidirectional transport of the conjugates. 3 Net tubular secretion of the sulphate, but not the glucuronide, conjugate was inhibited by the administration of probenecid.     

A peripheral 5-HT1D-like receptor involved in serotonergic induced hindlimb scratching in rats

The pharmacological characteristics of hindlimb scratching induced by serotonergic compounds were studied. We conclude that hindlimb scratching induced by serotonergic compounds is mediated by a serotonin1D (5-HT1D) or 5-HT1D-like receptor outside the blood-brain barrier because hindlimb scratching could be induced by s.c. injection of 5-methoxytryptamine (5-MeOT), 5-carboxamidotryptamine (5-CT), bufotenine, 5-hydroxytryptamine (5-HT) and tryptamine. These compounds have high affinity for 5-HT1A and 5-HT1D receptors. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), the 5-HT1C receptor agonist MK 212, and the mixed 5-HT1C/5-HT2 receptor agonists (dl)-1-(2,5 dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and quipazine did not induce hindlimb scratching. Rather, the latter compounds attenuated 5-MeOT-induced hindlimb scratching. The 5-HT releasing compounds fenfluramine and p-chloroamphetamine (PCA) inhibited whereas the 5-HT re-uptake inhibitors fluvoxamine and indalpine potentiated 5-MeOT-induced hindlimb scratching. 5-MeOT-induced hindlimb scratching could be inhibited dose dependently by the alpha 2-adrenoceptor blockers yohimbine and rauwolsince, which also have high affinity for 5-HT1D receptors, whereas the alpha 2-adrenoceptor blocker piperoxan only weakly counteracted hindlimb scratching. Haloperidol, apomorphine, morphine, clonidine and methiothepin strongly attenuated hindlimb scratching, atropine, naloxone and ICS 205930 attenuated it weakly whereas domperidone, methylatropine and mepyramine were inactive in doses up to 10 mg/kg. Hindlimb scratching induced by 5-MeOT was potentiated by the 5-HT receptor antagonists metergoline, methysergide, mesulergine, mianserin, ritanserin and xylamidine. Hindlimb scratching was not induced by i.c.v. injection of 5-MeOT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation of antiulcer activities of imidazo[1,2-alpha]pyridinyl-2-alkylaminobenzoxazoles and 5,6,7,8-tetahydroimidazo[1,2-alpha]pyridinyl-benzoxazoles with electron-topological (ET) method

The study presents structure-activity considerations of a series of imidazo[1,2-alpha]pyridiny-2-alkylaminobenzoxazoles(I) and 5,6,7,8-tetahydroimidazo[1,2-alpha]pyridinylbenzoxazoles(II) investigated for anti-stress ulcer activity with the electron-topological method. A series of 39 compounds including 24 active and 15 weakly active was studied. It is shown that the fragment determined by the electron-topological method in an active molecule is responsible for anti-stress ulcer activity. Quantitative structure-activity relationships with electron topological approach of these compounds are discussed in terms of the statistical program STATGRAF-7.0.     

Stimulation of acid and pepsin secretions in fistulated cats by dimaprit-like compounds

In the present paper the Authors describe the effects of dimaprit analogs on cat gastric acid and pepsin secretions. Such compounds are only weakly active as stimulants of H2-receptors, and studied as antagonists fail to inhibit acid and pepsin secretions evoked by dimaprit. The different mechanisms of action of dimaprit and histamine on H2-receptors are discussed.     

Time‐course measurements of drug concentrations in hair and toenails after single administrations of pharmaceutical products

Hair and nails are often used to prove long‐term intake of drugs in forensic drug testing. The aim of this study was to evaluate the effectiveness of drug testing using hair and nails and the feasibility of determining when drugs were ingested by measuring the time‐courses of drug concentrations in hair and toenails after single administrations of various drugs. Healthy subjects ingested four pharmaceutical products containing eight active ingredients in single doses. Hair and toenails were collected at predetermined intervals, and drug concentrations in hair and nails were measured for 12 months. The administered drugs and their main metabolites were extracted using micropulverized extraction with a stainless steel bullet and were analyzed using liquid chromatography/tandem mass spectrometry. Acidic compounds such as ibuprofen and its metabolites were not detected in both specimens. Acetaminophen, a weakly acidic compound, was detected in nails more frequently than in hair. The maximum concentration of allyl isopropyl acetylurea, a neutral compound, in nails was significantly higher than in hair. Nails are an effective specimen to detect neutral and weakly acidic compounds. For fexofenadine, a zwitterionic compound, and for most basic compounds, the maximum concentrations in hair segments tended to be higher than those in nails. The hair segments showing the maximum concentrations varied between drugs, samples, and subjects. Drug concentrations in hair segments greatly depended on the selection of the hair. Careful interpretation of analytical results is required to predict the time of drug intake. Copyright © 2016 John Wiley & Sons, Ltd.     

Acylmorphinans. A novel class of potent analgesic agents

A series of novel 2- and 3-acylmorphinans (8-14) was synthesized in our search for a potent analgesic agent with low addiction potential. The compounds were evaluated for antinociceptive potency and receptor binding affinity. Among these compounds, the levorotatory 3-acetyl-N-(cyclopropylmethyl)morphinan (12) was found to be an orally active analgesic, comparable in potency to morphine (1), yet only weakly able to substitute for morphine (1) in morphine-dependent rats.     

Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors.

A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.     

Novel inhibitors of Erm methyltransferases from NMR and parallel synthesis.

The Erm family of methyltransferases confers resistance to the macrolide-lincosamide-streptogramin type B (MLS) antibiotics through the methylation of 23S ribosomal RNA. Upon the methylation of RNA, the MLS antibiotics lose their ability to bind to the ribosome and exhibit their antibiotic activity. Using an NMR-based screen, we identified a series of triazine-containing compounds that bind weakly to ErmAM. These initial lead compounds were optimized by the parallel synthesis of a large number of analogues, resulting in compounds which inhibit the Erm-mediated methylation of rRNA in the low micromolar range. NMR and X-ray structures of enzyme/inhibitor complexes reveal that the inhibitors bind to the S-adenosylmethionine binding site on the Erm protein. These compounds represent novel methyltransferase inhibitors that serve as new leads for the reversal of Erm-mediated MLS antibiotic resistance.     

Actinopyrones A, B and C, new physiologically active substances. I. Producing organism, fermentation, isolation and biological properties

A strain of Streptomyces was found to produce new physiologically active substances. The active compounds were purified and separated into three substances named actinopyrones A, B and C. Actinopyrones exhibited coronary vasodilating activities in anesthetized dogs and weakly antimicrobial activities against some Gram-positive bacteria and dermatophytes.     

Conjugation of aspirin with vitamin C: uptake and stability studies

Aspirin and its prodrug obtained as conjugate with vitamin C (AA-Asp) were evaluated on human retinal pigment epithelium (HRPE) cells to investigate their ability to interact with the ascorbate transporter SVCT2 and their cellular uptake. Furthermore, stability in physiological fluids of these compounds was investigated. Transport and inhibition assays were performed by adding [¹⁴C]AA and the unlabeled compounds to plated HRPE cells. Intracellular accumulation was measured by incubating HRPE cells with the compounds, followed by HPLC analysis. For kinetic experiments, aspirin and AA-Asp were incubated in phosphate buffer, human plasma and whole blood. Aspirin was taken up into HRPE cells even though it was not able to interact with SVCT2; AA-Asp resulted as a competitive inhibitor of AA-transport weakly taken up into HRPE cells. AA- Asp resulted as a prodrug of aspirin when incubated in whole blood, but not when incubated in plasma: in this case the main metabolic product was salicylic acid.     

Design and synthesis of new tetrazolyl- and carboxy-biphenylylmethyl-quinazolin-4-one derivatives as angiotensin II AT1 receptor antagonists

A series of novel quinazolin-4-ones was designed and their molecular modeling simulation fitting to a new HipHop 3D pharmacophore model using CATALYST was examined. Several compounds showed significant high simulation fit values. The designed compounds were synthesized and eight of them were biologically evaluated in vitro using an AT1 receptor binding assay, where compound XX competed weakly against radiolabeled Sar1Ile8-angiotensin II (Ang II) binding, compounds XIV and XXII showed moderate competition, and compound XXV showed almost equal ability to displace radiolabeled Sar1Ile8-Ang II binding to AT1 receptors as losartan. In vivo biological evaluation study of compounds XIV, XXII, and XXV on both normotensive and hypertensive rats revealed that compound XXV demonstrated higher hypotensive and antihypertensive activity than the reference compound losartan. To obtain a highly active compound from a candidate set of only eight tested compounds illustrates the power and utility of our pharmacophore model.     

Inhibition of thrombin activity by selected natural products in comparison to neutrophil elastase

Enzymatic thrombin activity is significantly inhibited only by a few selected natural phenolic compounds (myricetin, rosmarinic acid, caffeic acid phenethyl ester) but more strongly by unsaturated fatty acids like erucic acid and oleic acids. Compared to the inhibitory potential against neutrophil elastase, thrombin activity is rather weakly inhibited by phenolic compounds and fatty acids. Because of the importance of thrombin as a ligand for protease-activated receptor 1 (PAR-1), which is involved in inflammation, the inhibition of thrombin activity by natural compounds might enhance the anti-inflammatory effects of neutrophil elastase inhibition.