Synthesis of N-(2-carboxy-thieno(2,3-b)pyridin-3-yl)-formamidines corresponding alkyl esters with antianaphylactic activity

A lot of N-(2-carboxy-thieno[2,3-b]pyridin-3-yl)formamidines especially in form of their amine salts--were synthesized by reaction of 3-amino-thieno[2,3-b]pyridine-2-carboxylic acids with dimethylformamide/phosphoroxide chloride or by reaction of 4-oxo-4H-pyrido[3',2':4,5]thieno[3,2-d]1,3- oxazines with amines. Carboxylic acid alkylesters of this structure were yielded from 3-amino-thieno[2,3-b]pyridine-2-carbonic acid alkylesters by reaction with dimethylformamide/phosphoroxide chloride or with N-formyl-piperidine or N-formyl-morpholine and phosphoroxide chloride. The compounds showed antianaphylactic activity.     

In vivo pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for AT2 receptors

L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl)[1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5- b]pyridine) is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT1 and AT2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.     

A nonpeptidyl growth hormone secretagogue

A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.     

6-aminoalkyloxazolo[4,5-b]pyridin-2(3H)-ones: synthesis and evaluation of antinoceptive activity

Series of 6-aminoalkyloxazolo[4,5-b]pyridin-2(3H)-ones incorporating structural modifications both in the alkyl chain and basic amino moiety were tested for their analgesic efficacy and safety in mice and rats. Two of the synthesised compounds, 4a (3-methyl-6-[(4-phenyl-1-piperazinyl)methyl]oxazolo[4,5-b]pyridin-2(3H)-one) and 12a (3-methyl-6?1-[2-(4-phenyl-1-piperazinyl)ethan-1-ol]?oxazolo[4,5-b]pyridin- 2(3H)-one) were found to be more potent than aspirin with ED50 values of 26 (16.1-42.4) and 15.5 (11.4-21.2) mg/kg po (mouse, phenylquinone writhing test) respectively and 6 (3.1-9.8) and 5.5 (3.5-8.8) mg/kg po (rat, acetic acid writhing test). Compounds 4a and 12a proved to be potent nonopioid nonantiinflammatory analgesics but unfortunately have sedative properties at relatively low doses (respectively 64 and 16 mg/kg po, mice).     

Effects of gavage versus dosed feed administration on the toxicokinetics of benzyl acetate in rats and mice

8-epi-prostaglandin F2 alpha stimulated contraction of human myometrial strips obtained from five different donors at the time of hysterectomy with a pEC50 value of 6.3 +/- 0.5. In paired strips from the same donors the pEC50 value for the selective TP receptor agonist U46619 ([1R-[1a,4a,5b(Z),6a(1E,3S*)]]-7-[6-(3- hydroxy-1-octenyl)-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid) was 8.3 +/- 0.4. In strips from four other donors 8-epi-prostaglandin F2 alpha was ineffective whereas the pEC50 for U46619 was 6.9 +/- 0.3. Responses to 8-epi-prostaglandin F2 alpha were unaffected by the selective DP receptor antagonist BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2- cyclohexyl-2-hydroxyethylamino)hydantoin) at 50 nM but were blocked by the selective TP receptor antagonist L670596 ((-)6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4- tetrahydrocarbazol-1-yl-acetic acid) at 50 nM. The pIC50 values obtained when the TP receptor antagonists GR 32191 ([1R- [1 alpha(Z),2 beta,3 beta,5 alpha]]-(+)-7-[5-[[(1,1'-biphenyl)-4- yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid), ICI D1542 ((4(Z)-6-[(2S,4S,5R)-2-[1-methyl-1-(2-nitro-4-tolyloxy)ethyl]- 4-(3-pyridyl)-1,3-dioxan-5-yl]hex-4-enoic acid), ICI 192605 (4(Z)-6-[(2,4,5-cis)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1,3- dioxan-5-yl]hexenoic acid), L670596 and SQ 29548 ([1S-(1 alpha,2 beta(5Z),3 beta,4 alpha]]-7- [3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid) were added cumulatively to strips pre-contracted with an EC80 concentration of 8-epi-prostaglandin F2 alpha were not significantly different from those obtained when an EC80 concentration of U46619 was used. The effects of 8-epi-prostaglandin F2 alpha on strips pre-contracted with an EC80 concentration of U46619 were not different from those of U46619 itself. It is concluded that in the non-pregnant human myometrium 8-epi-prostaglandin F2 alpha is a medium potency contractile agonist acting predominantly at the TP receptor.     

4-Diazinyl- and 4-pyridinylimidazoles: potent angiotensin II antagonists. A study of their activity and computational characterization

A series of N-[biphenylyl(tetrazolyl)methyl]-2-butylimidazoles containing variously substituted diazine or pyridine moieties either as their free bases or N-oxide derivatives attached to the 4-position of the imidazole ring was synthesized and tested for interaction with the AT1 receptors of rat adrenal cortex membranes (receptor binding assay). Some compounds were then chosen for further evaluation in vivo in the A II-induced pressor response in conscious normotensive rats. The most potent in the AT1 binding assay were found to be compounds in which the diazine or pyridine ring nitrogen is adjacent to the point of attachment between the two heteroaromatic rings such as 2-butyl-4-(3,6-dimethylpyrazin-2-yl)-1-[[2'-(1H-tetrazol-5-y l)-biphenyl-4- yl]methyl]-1H-imidazole (3b) or 2-butyl-4-[5-(methoxycarbonyl)pyrid-2-yl]-1-[[2'-(1H-tetrazol++ +-5- yl)biphenyl-4-yl]methyl]-1H-imidazole (6c). The binding affinities and oral activities of the pyridine N-oxide imidazoles in which a stabilizing group ortho to the pyridine ring nitrogen is present were markedly improved as in 2-butyl-4-[(3-methoxycarbonyl)-6-methyl-N-oxopyridin-2-yl]-1-[[2'- (1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole 31b. Molecular modeling studies were carried out to determine the molecular electrostatic potential values of related model systems and to correlate their receptor interaction energies with the observed activities of our compounds.     

Clinical experience with the holmium:YAG laser for transmyocardial laser revascularization and myocardial denervation as a mechanism

Several novel N-(4,5-diphenylthiazol-2-yl)-N'-aryl or alkyl (thio)ureas and N-(4,5-diphenylthiazol-2-yl)alkanamides were prepared as potential acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitors. Synthesis was accomplished by reaction of 2-amino-4,5-diphenylthiazole with the suitable isocyanate, isothiocyanate or acyl chloride. Some analogues without the 5-phenyl substituent or both the phenyl groups in 4 and 5 position of the thiazole ring were also prepared. Moreover, some bioisosters of the title compounds in which the thiazole ring was replaced by an imidazole were synthesized starting from the 2-amino-4,5-diphenyl-1H-imidazole. The ability of synthesized compounds to inhibit ACAT was evaluated in vitro by measuring the formation of cholesteryl[14C]oleate from cholesterol and [1-14C]oleoyl-CoA in rat liver microsomes. Among the tested compounds, only some thiazole ureas were able to inhibit ACAT in a reasonable degree. N-(4,5-diphenylthiazol-2-yl)- N'-[2,6-bis(2-methylethyl)phenyl] urea (11) and N-(4,5-diphenylthiazol-2-yl)-N'-n-butyl urea (16) were the most active compounds in the series showing IC50 values in the low micromolar range.     

Pyrrolo[1',2':1,2]imidazo[4,5-b]pyridines, pyrrolo- [2',1':2,3]imidazo[4,5-c]pyridines and pyrrolo[2,1-f]purines as potential benzodiazepine ligands

The synthesis of some 7,8,8a,9-tetrahydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-b]pyridin-6-ones, 5,5a,6,7-tetrahydro-8H-pyrrolo[2',1':2,3]imidazo[4,5-c]pyridin-8-ones and 7,8,8a,9-tetrahydro-6H-pyrrolo[2,1-f]purin-6-ones is reported. The structure of the obtained compounds has been assigned by means of 1H-NMR spectra assisted by NOESY measurements. In addition, the ability to displace [3H]-flunitrazepam binding from rat brain membranes is determined. Only the pyrrolopurine derivative 5d binds to the benzodiazepine receptor (BZR) with appreciable potency.     

Kinetic properties of the activator complexes plasmin--staphylokinase and plasmin(ogen)--streptokinase in vitro

The thiazole orange dye 1,1'-(4,4,8,8-tetramethyl-4, 8-diazaundecamethylene)-bis-4-[(3-methyl-2,3-dihydro-2(3H)-benzo-1 ,3-thiazolylidene)methyl]quinolinium tetraiodide (TOTO) binds to double-stranded DNA (dsDNA) in a sequence selective bis-intercalation. We have examined the binding of derivatives of TOTO with different substituents on the benzothiazole ring. The analogues are the following: 1,1'-(4,4,8,8-tetramethyl-4, 8-diazaundecamethylene)-[4-[3-(benzyl-2, 3-dihydro-2-(3H)-benzothiazolylidene)methyl]quinolinium]-[4-[3-(++ +methy l-2, 3-dihydro-2-(3H)-benzothiazolylidene)methyl]quinolinium]tetraio dide (TOTOBzl) and 1,1'-(4,4,8,8-tetramethyl-4, 8-diazaundecamethylene)-bis-4-[(3-ethyl-2,3-dihydro-2(3H)-benzo-1, 3-thiazole)methyl]quinolinium tetraiodide (TOTOEt). In this paper, we report the synthesis of TOTOBzl and TOTOEt together with the one- and two-dimensional 1H NMR investigations of complexes between these TOTO analogues and the dsDNA oligonucleotide d(CGCTAGCG)2. Both analogues yield extremely stable complexes in which each chromophore is sandwiched between two base pairs in a (5'-CpT-3'):(5'-ApG-3') site. The linker spans over two base pairs in the minor groove. The benzyl group in TOTOBzl and the ethyl groups in TOTOEt is pointing outward in the major groove.     

Cross-linking of proteins by Maillard processes--model reactions of D-glucose or methylglyoxal with butylamine and guanidine derivatives

Advanced Maillard reaction in proteins leads to formation of covalently cross-linked aggregates the chemical nature of which is largely unknown. From model reactions of methylglyoxal and butylamine with creatine or alpha-N-acetyl-L-arginine, one main product each was isolated. These two compounds were identified, on the basis of unequivocal spectroscopic evidence, as 2-[(5-butylimino-4-methyl-4,5-dihydro-1H-2-imidazolyl)(methyl)amin o]acetic acid and 2-acetylamino-5-[(5-butylimino-4-methyl-4,5-dihydro-1H-2-imidazoly l)amino]pentanoic acid, respectively. Using D-glucose instead of methylglyoxal, two main products each were obtained from reaction with the respective guanidine derivative. The spectroscopic data definitively establish the formation of the diastereoisomeric 2-[(4-butyl-6,7-dihydroxy-4,5,6,7,8,8a-hexahydroimidazo[4,5-b]a zepin-2-yl)(methyl)amino]acetic acid from the reaction with creatine, and of the diastereoisomeric 2-acetylamino-5-[(4-butyl-6,7-dihydroxy-4,5,6,7,8,8a-hexahydroimidazo [4,5-b]azepin-2-yl)amino]pentanoic acid from the reaction with alpha-N-acetyl-L-arginine. All products were isolated in fairly good yield and represent 1:1:1 adducts of the respective reaction partners. Formation of these compounds thus constitutes an efficient reaction pathway for linking primary amines to guanidine derivatives. It seems justified, therefore, to expect cross-linking of proteins by action of reducing carbohydrates to proceed analogously.     

Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor

L-745,870,(3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H- pyrollo[2,3-b] pyridine, was identified as a selective dopamine D4 receptor antagonist with excellent oral bioavailability and brain penetration. L-745,870 displaced specific binding of 0.2 nM [3H] spiperone to cloned human dopamine D4 receptors with a binding affinity (Ki) of 0. 43 nM which was 5- and 20-fold higher than that of the standard antipsychotics haloperidol and clozapine, respectively. L-745,870 exhibited high selectivity for the dopamine D4 receptor (>2000 fold) compared to other dopamine receptor subtypes and had moderate affinity for 5HT2, sigma and alpha adrenergic receptors(IC50 < 300 nM). In vitro, L-745,870 (0.1-1 microM) exhibited D4 receptor antagonist activity, reversing dopamine (1 microM) mediated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2) stimulation of [35S] GTPgammaS binding and 3) stimulation of extracellular acidification rate, but did not exhibit any significant intrinsic activity in these assays. Although standard antipsychotics increase dopamine metabolism or plasma prolactin levels in rodents, L-745,870 (相似文献   

L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioral tests

This study examined the high-affinity, selective dopamine D4 receptor antagonist, L-745,870 (3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2, 3-b]pyridine) in rodent behavioral models used to predict antipsychotic potential and side-effect liabilities in humans. In contrast to the classical neuroleptic, haloperidol, and the atypical neuroleptic, clozapine, L-745,870 failed to antagonize amphetamine-induced hyperactivity in mice or impair conditioned avoidance responding in the rat at doses selectively blocking D4 receptors. Furthermore, L-745,870 failed to reverse the deficit in prepulse inhibition of acoustic startle responding induced by the nonselective dopamine D2/3/4 receptor agonist apomorphine, an effect which was abolished in rats pretreated with the D2/3 receptor antagonist, raclopride (0.2 mg/kg s.c.). L-745,870 had no effect on apomorphine-induced stereotypy in the rat but did induce catalepsy in the mouse, albeit at a high dose of 100 mg/kg, which is likely to occupy dopamine D2 receptors in vivo. High doses also impaired motor performance; in rats L-745,870 significantly reduced spontaneous locomotor activity (minimum effective dose = 30 mg/kg) and in mice, L-745,870 reduced the time spent on a rotarod revolving at 15 rpm (minimum effective dose = 100 mg/kg). Altogether these results suggest that dopamine D4 receptor antagonism is not responsible for the ability of clozapine to attenuate amphetamine-induced hyperactivity and conditioned avoidance responding in rodents. Furthermore, the lack of effect of L-745,870 in these behavioral tests is consistent with the inability of the compound to alleviate psychotic symptoms in humans.     

Systemic candidiasis with acute Epstein-Barr virus infection

The binding of a classical cannabinoid agonist, [3H]R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2 ,3-de]-1,4-benzoxazin-6-yl)(1-napthalenyl)methanone monomethanesulfonate ([3H] WIN55212-2), and a selective cannabinoid receptor (CB1) antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4-meth yl-1H-pyrazole-3-carboxamide hydrochloride ([3H]SR141716A), to rat cannabinoid receptors was evaluated using rat cerebellar membranes. Guanine nucleotides inhibited [3H]WIN55212-2 binding by approximately 50% at 10 microM and enhanced [3H]SR141716A binding very slightly. In the same tissue, the binding of guanosine 5'-O-[gamma-[35S]thio]triphosphate ([35S]GTP-gamma-S) was characterized and the influence of cannabinomimetics evaluated on this binding. Cannabinoid receptor agonists enhanced [35S]GTP-gamma-S binding, whereas SR141716A was devoid of action by itself but antagonized the action of cannabinoid receptor agonists. The good correlation obtained between the half maximum efficient concentration (EC50) values in [35S]GTP-gamma-S binding and the IC50 values [3H]WIN55212-2 binding shows that [35S]GTP-gamma-S binding could be a good functional assay for brain cannabinoid receptors.     

Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of potential prodrugs of benzimidazole-7-carboxylic acids

In order to improve the oral bioavailability (BA) of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimid azole - 7-carboxylic acid (3: CV-11194) and 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]-1H-benzimidazole-7-carboxylic acid (4: CV-11974), novel angiotensin II (AII) receptor antagonists, chemical modification to yield prodrugs has been examined. After selective tritylation of the tetrazole rings in 3 and 4, treatment of N-tritylated benzimidazole-7-carboxylic acids (6, 7) with a variety of alkyl halides, followed by deprotection with hydrochloric acid, afforded esters of 3 and 4. Mainly 1-(acyloxy)alkyl esters and 1-[(alkoxycarbonyl)oxy]alkyl esters, double ester derivatives, were synthesized. Their inhibitory effect on AII-induced pressor response in rats and oral BA were investigated. (Pivaloyloxy)methyl and (+/-)-1-[[(cyclohexyloxy)-carbonyl]oxy]ethyl esters of 3 and 4 showed marked increases in oral bioavailability which significantly potentiated the inhibitory effect of the parent compounds on AII-induced pressor response. Among them, (+/-)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2- ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimida zole- 7-carboxylate (10s, TCV-116) was selected as a candidate for clinical evaluation.     

Synthesis, properties and biological evaluation of substituted furo[3,2-e] and pyrano[3,2-e]pyrido[4,3-b]indoles

Furo[3,2-e]- and pyrano[3,2-e]pyrido[4,3-b] indoles were synthesized from 1,4,5-trisubstituted 8-hydroxy-5H-pyrido[4,3-b]indoles. The intermediates, 10-chloro-6H-furo[3,2-e]pyrido[4,3-b]indole (11), 10-chloro-2,6-dihydro-1H-furo[3,2-e]pyrido-[4,3-b]indole (10) and 11-chloro-2,3-dihydro-3H,7H-pyrano[3,2-e]pyrido[4,3-b]indole (15), were substituted by diamines under thermal conditions (180 degrees C). In contrast, 11-chloro-3H,7H-pyrano[3,2-e]pyrido[4,3-b]indole (14), 9-allyl-1-chloro-4,5-dimethyl-5H-pyrido[4,3-b]indole (9a) and 8-propargyloxy-4,5-dimethyl-5H-pyrido[4,3-b]indole (8) led mainly to 1-aminosubstituted 8-hydroxy-5H-pyrido[4,3-b]indole derivatives resulting from an unexpected C3 unit elimination. When examined in three tumour cell lines (L1210 leukaemia, the B16 melanoma and the MCF7 breast adenocarcinoma) the new amino substituted furo[3,2-e]-, dihydrofuro[3,2-e]- and dihydropyrano[3,2-e]-pyrido[4,3-b]indole derivatives revealed cytotoxic properties, especially important for the 2,6-dihydro-1H-furo[3,2-e]pyrido[4,3-b]indole series. The most active compound (12b) significantly inhibits both DNA topoisomerases I and II, and is as potent as Adriamycin at inhibiting cell proliferation and inducing a massive accumulation of L1210 cells in the G2 + M phase of the cell cycle. However, 12b was less active than Adriamycin when tested in vivo against P388 leukaemia or the B16 melanoma tumour models.     

Characterization of a specific binding site for angiotensin II in chicken liver

We have characterized a specific binding site for angiotensin II (AngII) in chicken liver membranes. Pseudo-equilibrium studies at 22 degrees C for 30 min have shown that this binding site recognizes AngII with a high affinity (pKD of 8.13 +/- 0.21). The binding sites are saturable and relatively abundant (maximal binding capacity varies from 0.318 to 0.88 pmol/mg of protein). Nonequilibrium kinetic analyses at 22 degrees C revealed a calculated kinetic pKD of 8.77 +/- 0.20. The binding site is pharmacologically distinct from the classic AngII receptors AT1 and AT2. Competitive binding studies with chicken liver membranes demonstrated the following rank order of effectiveness: AngII (human; Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) > AngI(Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) > AngIII(Arg-Val-Tyr-Ile-His-Pro-Phe) > AngIV (Val-Tyr-Ile-His-Pro-Phe) > Ang(1-7) (Asp-Arg-Val-Tyr-Ile-His-Pro) > PD123319 (1-[4(dimethylamino)3-methylphenyl] methyl-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-6-carboxylic acid) > DuP753 (2-n-butyl-4-chloro-5 hydroxymethyl-1-[(2'-1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole. This atypical AngII binding site (chicken AT) was sensitive to increasing concentrations of DTT and Mn2+. The structure-activity relationship on position 1 of AngII showed that the primary N-terminal amine was essential for binding affinity ([Asp1]AngII > [Suc1]AngII > or = [Sar1]AngII), but modifications of the side chain in position 1 had less influence on the affinity ([Gly1]AngII > [Cys1]AngII approximately [aminoisobutyryl1]AngII approximately [Ser1]AngII > > > [Sar1]AngII). The presence of substantial quantities of this binding site in chicken liver membranes suggests the possibility that the chicken AT may play an important, yet unrecognized, role in the renin-angiotensin system.     

Evidence for a 1,2-hydride shift in the microsomal metabolism of the heterocycle L-158,338, a nonpeptide angiotensin II receptor antagonist

L-158,338 is an imidazo[4,5-b]pyridine derivative that is a potent and highly selective angiotensin II receptor antagonist. Rat liver microsomal metabolism of [C6-3H]L-158,338 gave a major metabolite that was monohydroxylated at the C6 position of the imidazo-pyridine but showed partial retention of the radiolabel. This biotransformation necessitated a shift of the radiolabel from the C6 position to another site within the molecule. We have investigated the mechanism of this biotransformation using 3H-, 3H/14C-, and 2H-labeled L-158,338. Metabolites were identified by FAB/MS, LC/MS, and 1H-NMR. Results of these studies show that the microsomal metabolism of L-158,338 to its C6-monohydroxylated derivative was mediated by a 1,2 hydride shift.     

Childhood hypersensitivity pneumonitis probably caused by cat hair

One of the mechanisms for multidrug resistance (MDR) of tumors is an overexpression of the P-glycoprotein (P-gp). The cytostatic agent daunorubicin was labeled with carbon-11 to probe P-gp with PET. An enzymatic route for the conversion of carminomycin to [4-methoxy-11C]daunorubicin ([4-methoxy-11C]DNR) was investigated, since attempts failed to prepare daunorubicin chemically using [11C]methyl iodide. In the enzymatic synthesis methylation was accomplished by S-adenosyl-L-[methyl-11C]methionine ([11C]SAM), which was synthesized from L-[methyl-11C]methionine. This methylation is catalyzed by carminomycin-4-O-methyltransferase (CMT). The overall radiochemical yield of [4-methoxy-11C]DNR is 1% (EOB), with a total synthesis time of 75 min. In conclusion, [4-methoxy-11C]DNR can be successfully prepared from carminomycin and [11C]SAM using enzymes.     

Pyrazolopyridine derivatives act as competitive antagonists of brain adenosine A1 receptors: [35S]GTPgammaS binding studies

The effects of adenosine receptor ligands and three novel pyrazolopyridine derivatives on guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding to rat cerebral cortical membranes were examined. [35S]GTPgammaS binding was stimulated in a concentration dependent manner by several adenosine receptor agonists. The adenosine A2a receptor selective agonist, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), was ineffective confirming specificity for adenosine A1 receptor activation. 2-Chloro-N6-cyclopentyladenosine (CCPA; 10(-7) M)-stimulated [35S]GTPgammaS binding was inhibited by xanthine and pyrazolopyridine based adenosine receptor antagonists. The concentration-response curve for CCPA-stimulated [35S]GTPgammaS binding was shifted to the right with increasing concentrations of antagonist without significant changes in maximal response. Schild analyses determined pK(B) values of 8.97, 8.88, 8.21, 8.16, 7.79 and 7.65 for 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), (R)-1-[(E)-3-(2-phenylpyrazolo[1,5a]pyridin-3-yl) acryloyl]-2-piperidine ethanol (FK453), 6-oxo-3-(2-phenylpyrazolo[1,5a]pyridin-3-yl)-1(6H)-pyridazinebutyric+ ++ acid (FK838), 9-chloro-2-(2-furyl)[1,2,4]triazolo-[1,5c]quinazolin-5-amine (CGS 15943), 8-cyclopentyl-1,3-methylxanthine (CPT) and (R)-1-[(E)-3-(2-phenylpyrazolo[1,5a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352), respectively. Schild slopes were close to unity, confirming that these novel pyrazolopyridine derivatives act as competitive antagonists at rat brain adenosine A1 receptors.