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Biomedical subjects

C E Müller

Publications and source records attributed to C E Müller.

At least 37 records · Page 2Linked to original sources
PubMed1996

Chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives: structure-activity relationships of potent, highly stereoselective A1-adenosine receptor antagonists.

A series of 33 novel, mostly chiral pyrrolo[2,3-d]pyrimidine and pyrimido[4,5-b]indole derivatives has been synthesized and investigated in radioligand binding assays at the high-affinity adenosine receptor (AR) subtypes A1 and A2a. The compounds can be envisaged as adenine and hypoxanthine analogs lacking the nitrogen in the 7-position (7-deazaadenines and 7-deazahypoxanthines). 7-Deazaadenines were much more potent than 7-deazahypoxanthines at AR with A1AR affinities in the low-nanomolar range, extraordinarily high selectivity for the rat brain A1AR versus the A2aAR (several thousandfold), and high stereoselectivity (up to 96-fold). Pyrimido[4,5-b]indoles were more potent A1AR antagonists compared to pyrrolo[2,3-d]pyrimidines. Compound 34a (APEPI) is one of the most potent and most selective nonxanthine A1AR antagonists known to date (Ki = 2.8 nM, > 2000-fold A1-selective). A new class of very potent A1AR antagonists has been identified, namely, 2-phenyl-7-deazaadenines bearing a substituent at the exocyclic amino group (N4-substituted pyrrolo[2,3-d]pyrimidines). (R)-N- (1-Phenylethyl)-4-amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin e (DPEAP, 17a) showed a Ki value of 6.7 nM at A1AR and > 4000-fold A1 selectivity. Different binding modes are postulated for the N4-substituted 4-aminopyrrolo[2,3-d]pyrimidines (e.g., 17a) and the 7-substituted derivatives (e.g., 1a), based on a comparison of steric, electronic, and hydrophobic properties of the two classes of compounds. Water solubility and lipophilicity have been determined for selected compounds. 4-Amino-5,6-dimethyl-2-(3-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (4a) showed the highest water solubility/A1AR affinity ratio of 368 in the present series, over 2000-fold A1 selectivity, and 64-fold stereoselectivity (R > S). Therefore, 4a should be an interesting compound for in vivo evaluation.

Adenine↗
PubMed1995

Tricyclic theophylline derivatives with high water-solubility: structure-activity relationships at adenosine receptors, phosphodiesterases, and benzodiazepine binding sites.

A series of tricyclic, highly water-soluble theophylline derivatives (pyrimido[2,1-f]-theophyllines) containing a basic side chain was investigated in rat brain A1- and A2 adenosine receptor binding assays, phosphodiesterase assays, and benzodiazepine binding studies. Among the new compounds adenosine receptor antagonists with affinities in the same range as the parent compound theophylline were identified. In addition, some compounds were selective for the A1 adenosine receptor subtype. The compounds generally exhibited lower inhibitory activity at brain phosphodiesterases than the parent theophylline. Two compounds were found to show an about 10-fold affinity for benzodiazepine binding sites compared with caffeine and theophylline.

Animals↗
PubMed1994

Synthesis and structure-activity relationships of deazaxanthines: analogs of potent A1- and A2-adenosine receptor antagonists.

A set of 22 9-deazaxanthines (pyrrolo[3,2-d]pyrimidine-2,4-diones) and three 7-deazaxanthines (pyrrolo[2,3-d]pyrimidine-2,4-diones) with various substituents in the 1-, 3-, 7- or 9-, and 8-positions was synthesized and investigated in A1 and A2a adenosine receptor binding assays at rat brain cortical membranes and rat brain striatal membranes, respectively. 9-Deazaxanthines showed structure-activity relationships that were similar to those of xanthines. They were about equipotent to the corresponding xanthines at A2a adenosine receptors. 9-Deazaxanthines were generally at least 2-3-fold more potent than xanthines at A1 receptors and therefore exhibited higher A1 selectivities compared to the xanthines. 1,3-Dimethyl-8-(2-naphthyl)-9- deazaxanthine (19e) showed high affinity (Ki = 26 nM) and selectivity for A1 adenosine receptors. A hydroxyl function at N7 of 9-deazaxanthines was unfavorable for A1 and A2a receptor binding. 7-Deazaxanthines were considerably less potent compared to xanthines and to 9-deazaxanthines at both receptor subtypes.

Animals↗
PubMed1994

Immobilization, a risk factor for urinary tract stones in children. A case report.

Immobilization causes bone dissolution leading to hypercalcemia and hypercalciuria in children. We report the case of a 10-year-old boy who developed 2 stones in the pelvis off his left healthy kidney after only 8 days of immobilization. He was on bedrest after pyeloplasty done for a ureteropelvic junction obstruction on the right side. Compared to references in literature our patient showed stone formation very early during the course of immobilization. Temporary hypercalciuria and stone formation are well documented because of underlying kidney disease. The risk factors of immobilization-induced hypercalciuria and hypercalcemia are discussed together with possible treatment and prophylaxis of this pathology.

Calcium↗
PubMed1994

Amino-substituted 1,8-naphthyridines and pyrido[2,3-d]pyrimidines: new compounds with affinity for A1- and A2-adenosine receptors.

Two novel classes of adenosine receptor (AR) antagonists, 4-amino-1,8-naphthyridines and 5-aminopyrido[2,3-d]pyrimidines, have been identified and investigated in radioligand binding assays. The compounds exhibit affinities for A1 and A2a AR of rat brain in the micromolar range. 1,8-Naphthyridines are non-selective, or somewhat selective for either A1- or A2 AR. Pyrido[2,3-d]pyrimidines are several-fold selective for A1 AR, the most potent and selective compound being 5-n-butylamino-1,3-dimethyl-1,2,3,4-tetrahydropyrido-[2,3-d]pyr imi dine-2,4-dione (12) with a Ki value of 1.8 microM at A1 AR and greater than 10-fold A1-selectivity.

Animals↗
PubMed1993

Stimulation of calcium release by caffeine analogs in pheochromocytoma cells.

Caffeine (EC50 approximately 20 mM) causes a maximal 400% increase in intracellular calcium ion concentration ([Ca2+]i) in pheochromocytoma PC12 cells. A range of caffeine analogs in which methyl groups at the 1, 3, and 7 positions were replaced with relatively nonpolar (ethyl, allyl, propyl, propargyl) or polar (CH2COOH, CH2CH2OH, CH2CN, CH2OCH3) substituents were tested at a 10 mM concentration. Many analogs were as efficacious or only somewhat less efficacious than 10 mM caffeine. Certain analogs with polar substituents had no effect. Disubstituted xanthines were less efficacious (theophylline, paraxanthine) than caffeine or were ineffective (theobromine). 1-Propyl-3,7-dimethylxanthine (EC50 4 mM) and 1-propargyl-3,7-dimethylxanthine (EC50 5 mM) were several-fold more potent than caffeine in causing elevation of [Ca2+]i and the latter was at least as efficacious.

Animals↗
PubMed1993

Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthines unsubstituted at the 3-position: structure-activity relationships at adenosine receptors.

Synthetic procedures for the preparation of various 3-unsubstituted xanthines, including paraxanthine analogs (1,7-disubstituted xanthines) and 1,8-disubstituted xanthines, were developed. Silylation of 1-substituted xanthines followed by alkylation at the 7-position provides a facile route to paraxanthine analogs. Regioselective alkylation of tris(trimethylsilyl)-6-aminouracil provides 3-substituted 6-aminouracils, which are converted to 1,8-disubstituted xanthines by standard procedures. The ring closure of 3-substituted 5-cyclopentanecarboxamido- and 5-(benzoylamino)-6-aminouracils requires drastic reaction conditions. Affinity for brain A1 and A2 adenosine receptors was determined in binding assays for these and other xanthines with substituents in 1-, 3-, 7-, 8-, and 9-positions. Substitution at the 1-position was necessary for high affinity at adenosine receptors. 1,3-Disubstituted xanthines generally had higher affinity than 1,7-disubstituted xanthines. 1,8-Disubstituted xanthines had high affinity for adenosine receptors; some were highly selective for A1 receptors.

Animals↗
PubMed1993

Adenosine receptors and their modulators.

The identification and characterization of adenosine receptors and the development of potent, receptor subtype-selective agonists and antagonists has been an active area of research for the past 20 years. Major recent advances in the field have been the cloning of several adenosine receptor subtypes of different species, including the discovery of a new subtype, designated A3, the discovery and development of new agonists and antagonists, particularly those with selectivity for the A2a adenosine receptor, the characterization of signal transduction pathways, and the development of agents which act indirectly on the adenosine receptor system. The present article focusses on aspects of pharmaceutical/medicinal chemistry related to adenosine receptors.

Amino Acid Sequence↗
PubMed1991

Caffeine analogs: structure-activity relationships at adenosine receptors.

Caffeine and analogs that contain ethyl, propyl, allyl, propargyl and other substituents in place of methyl at 1-, 3- and 7-positions were antagonists at the two major classes (A1 and A2) of adenosine receptors. Potency at both receptors increased as methyls were replaced with larger substituents. Certain analogs with only one of the three methyl groups of caffeine replaced by larger substituents were somewhat selective for A2 receptors. None of the analogs were particularly selective for A1 receptors. The presence of polar entities in the substituent at the 1- or 7-position was poorly tolerated at adenosine receptors. Activity of caffeine analogs at A1 and A2 adenosine receptors in a variety of systems and cell types is presented and summarized.

Adenylyl Cyclases↗
PubMed1991

Methylxanthines block antigen-induced responses in RBL-2H3 cells independently of adenosine receptors or cyclic AMP: evidence for inhibition of antigen binding to IgE.

Activation of a novel adenosine receptor in a rat tumor mast cell line (RBL-2H3 cells) elicits a transient generation of inositol 1,4,5-trisphosphate and an equally transient increase in the level of free cytosol Ca++: Such responses promote little exocytosis, but markedly enhance the secretory response to antigen. A variety of xanthine adenosine receptor antagonists did not suppress the responses to the adenosine analog 5-N-ethylcarboxamidoadenosine. However, 3-isobutyl-1-methylxanthine (IBMX) and certain related xanthines inhibited antigen (dinitrophenylated bovine serum albumin, DNP-BSA)-induced generation of inositol phosphates, the increase in level of free cytosolic Ca++ and exocytosis in RBL-2H3 cells that were primed with a monoclonal DNP-specific immunoglobulin E (from hybridoma H1 DNP-epsilon-26.82). The same compounds inhibited the binding of antigen to cell attached DNP-specific IgE in a highly selective manner. Incorporation of an aromatic or cycloalkyl group in the 8-position of IBMX or theophylline, for example, resulted in compounds that were more potent inhibitors than the parent compounds. Conversely, substituents in the 7- or 9-position of IBMX resulted in inactive compounds. 1,3-Diethylxanthine and 1,3-dipropylxanthine had no activity, suggesting that substituents as large as ethyl or propyl are not tolerated at the 1-position. Inhibition by IBMX was not observed when cells were activated by nonimmunological stimulants or when cells were primed with certain other monoclonal preparations of DNP-specific IgE and stimulated by DNP-BSA.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1990

7-Deaza-2-phenyladenines: structure-activity relationships of potent A1 selective adenosine receptor antagonists.

A series of derivatives of 7-deazapurines with varying substituents in the 2-, 6-, and 9-position was synthesized in an attempt to improve the adenosine receptor affinity and A1 or A2 selectivity. The adenosine receptor affinities were assessed by measuring the inhibition of [3H]-(R)-N6-(phenylisopropyl) adenosine (R-PIA) binding to rat brain A1 and inhibition of [3H]-5'-(N-ethylcarboxamido)adenosine (NECA) binding to rat striatum A2 adenosine receptors. A selected set of compounds representing the main structural variations was further examined in adenosine receptor coupled adenylate cyclase assays. All tested compounds antagonized the inhibition of adenylate cyclase elicited by interaction of R-PIA with A1 receptors in rat fat cell membranes and the activation of adenylate cyclase elicited by interaction of NECA with A2 receptors of pheochromocytoma PC12 cell membranes. The results indicate that 7-deazahypoxanthines have a potential for A2 selectivity, while all 7-deazaadenines are A1 selective. Introduction of a phenyl residue in the 2-position of 7-deazaadenines increases A1 activity tremendously. 2-(p-Chlorophenyl)-7,8-dimethyl-9-phenyl-7-deazaadenine (29) is potent and specific for the A1 receptors of rat brain (Ki = 122 nM), having no affinity for the A2 receptors of rat striatum. The compound has low activity at the A2 receptors of rat PC12 cell membranes where it appears to act as a noncompetitive inhibitor. A 1-phenylethyl substituent at the 9-position was found to be superior to a phenyl residue in terms of A1 affinity. The most potent A1 antagonist in the present series is the highly A1 selective (790-fold) (R)-7,8-dimethyl-2-phenyl-9-(1-phenylethyl)-7-deazaadenine (31, Ki = 4.7 nM), which is 30-35 times more potent at A1 receptors than its S enantiomer. The solubility of six of the potent 7-deaza-2-phenyladenines was determined by means of an A1 binding assay. Chloro substitution of the 2-phenyl ring appeared to improve the solubility as well as the solubility over A1 affinity ratio of 9-phenyl- and 9-(1-phenylethyl)-substituted 7-deazadenines.

Adenine↗
PubMed1989

[Synthesis of computer graphic calculated high-anti-fixed pyrimidine nucleoside analogs with potential virostatic and antineoplastic action].

Novel C-5 substituted 6,2'-anhydrouridines 5a-e are synthesized from the hitherto unknown monosubstituted ribofuranosylbarbituric acid derivatives 4a-e. These molecules are high-anti-fixed by a 6,2'-linkage and were assumed to show antiviral and antineoplastic effects. In cell culture test systems, however, none of these biological activities could be detected up to now.

Antineoplastic Agents↗
PubMed1984

Idiotope regulation by isotype switch variants of two monoclonal antiidiotope antibodies.

Previous work has shown that the injection of antiidiotope antibodies specific for idiotopes of the germline-encoded anti-(4-hydroxy-3-nitro-phenyl) acetyl (NP) antibody B1-8 enhanced or suppressed the expression of B1-8 idiotopes in subsequent humoral anti-NP responses, depending on the dose and perhaps also the isotype of the injected antibody. To formally answer the question of whether the isotype of an antiidiotope determines its effector function in this type of idiotypic control, we have performed regulatory experiments with isotype switch variants selected from two hybridomas secreting anti-B1-8 idiotopes of CBA (Ighj) and C57BL/6 (Ighb) origin. The antibodies of each variant family differ from each other only in the constant region of the heavy chain. The results show that, irrespective of whether an antiidiotope antibody belongs to the IgG1, IgG2b, IgG2a, or IgE class, a 10-ng dose enhances idiotope expression whereas a dose of 10 micrograms exerts a suppressive effect. It emerges from the present and parallel data that the expression of antibody V regions resembling idiotypically that of antibody B1-8 can be enhanced and suppressed by any of four antiidiotope antibodies that recognize distinct idiotopes on those V regions. This suggests that the initial step in the regulatory process induced by an antiidiotope is its binding to antibody V regions carrying the target idiotope. The antiidiotopes preferentially regulate the expression of antibodies that coexpress with the target idiotope other B1-8 idiotopes, despite the fact that some B1-8 idiotopes are also expressed independently of each other in anti-NP responses of idiotypically unmanipulated mice. This finding may reflect high affinity binding of the antiidiotopes to the target against which they were originally raised (i.e., antibody B1-8) or, more likely, a preferential recognition of B1-8-like V regions by regulatory T cells.

Animals↗
PubMed1983

Isolation of immunoglobulin class switch variants from hybridoma lines secreting anti-idiotope antibodies by sequential sublining.

The combination of a sensitive radioimmunoassay with a simple limiting dilution approach designated as sequential sublining (ssl) allowed us to isolate spontaneous class switch variants from two hybridoma lines secreting monoclonal anti-idiotope antibodies against a germ-line encoded antibody with defined hapten-binding specificity. We obtained two families of antibodies, one of which consists of IgG1, IgG2b, and IgG2a, the other consisting of IgG1, IgG2b, IgG2a, and IgE antibodies. The members of a family possess identical anti-idiotypic specificity. We describe serologic and biochemical properties of the class switch variants as well as the frequency and order of "forward" and "reverse" switching, and we compare the ssl approach to other related methods. The ssl allows the rapid isolation of somatic mutants, which have acquired a new predefined antigenic determinant, without complicated equipment and even when the frequency of the mutants is as low as 10(-6) or 10(-7).

Animals↗
PubMedDate not supplied

A1 adenosine receptors and their ligands: overview and recent developments.

Potent adenosine receptor (AR) agonists and antagonists with high selectivity for the A1AR subtype have been developed during the past decades. However, some of the compounds considered to be selective may not be as selective in humans as in rats, and may not be very selective versus the new AR subtypes A3 or A2B. Partial agonists have been developed that may exhibit fewer side effects than full agonists. Low water solubility of many A1 antagonists remains a problem. A1 AR antagonists can be classified as neutral antagonists or inverse agonists; the pharmacological consequences of inverse agonism versus neutral antagonism will have to be the subject of future investigations. Some medicinal plants (e.g. Hypericum perforatum and Valeriana officinalis) contain compounds that are antagonists or partial agonists at A1 ARs; effects on ARs may contribute to their pharmacological activity. 18F- and 11C-labeled A1 AR antagonists have been developed for positron emission tomography studies.

Animals↗