Biomedical subjects

C Hildebrandt

Publications and source records attributed to C Hildebrandt.

12 recordsLinked to original sources

PubMed2001

NF449: a subnanomolar potency antagonist at recombinant rat P2X1 receptors.

Antagonistic effects of the novel suramin analogue 4,4',4",4"'-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF449) were studied on contractions of the rat vas deferens elicited by alpha,beta-methylene ATP (alphabetameATP; mediated by P2X1 receptors), contractions of the guinea-pig ileal longitudinal smooth muscle elicited by alphabetameATP (mediated by P2X3 receptors) or adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS; mediated by P2Y1 receptors), ATP-induced increases of [Ca2+]i in human embryonic kidney (HEK) 293 cells (mediated by P2Y2 receptors), inward currents evoked by ATP in follicle cell-free Xenopus laevis oocytes expressing rP2X1 or rP2X3 receptors and degradation of ATP by ecto-nucleotidases in folliculated Xenopus laevis oocytes. In addition, NF449 was examined for its P2 receptor specificity in rat vas deferens (alpha1A-adrenoceptors) and guinea-pig ileum (histamine H1 and muscarinic M3 receptors). At native (pIC50=7.15) and recombinant (pIC50=9.54) P2X1 receptors, NF449 was a highly potent antagonist. The P2X3 receptors present in guinea-pig ileum (pIC50=5.04) or expressed in oocytes (pIC50 approximately 5.6) were much less sensitive for NF449. It also was a very weak antagonist at P2Y1 receptors in guinea-pig ileum (pIC50=4.85) and P2Y2 receptors in HEK 293 cells (pIC50=3.86), and showed very low inhibitory potency on ecto-nucleotidases (pIC50<3.5). NF449 (100 microM) did not interact with alpha1A-adrenoceptors or histamine H1 and muscarinic M3 receptors. Thus, the antagonism by NF449 is highly specific for P2 receptors. In conclusion, the subnanomolar potency at rP2X1 receptors and the rank order of potency, P2X1 >> P2X3 > P2Y1 > P2Y2 > ecto-nucleotidases, make NF449 unique among the P2 receptor antagonists reported to date. NF449 may fill the long-standing need for a P2X1-selective radioligand.

Animals↗

PubMed2000

The novel heteromeric bivalent ligand SB9 potently antagonizes P2Y(1) receptor-mediated responses.

Effects of 6-[(4,6,8-trisulfo-1-naphthyl)iminocarbonyl-1, 3-(4-methylphenylene)iminocarbonyl-1, 3-phenylene-azo]-pyridoxal-5'-phosphate (SB9), a heterodimeric bivalent ligand consisting of pyridoxal-5'-phosphate and the suramin monomer, were studied on contractions of the rat vas deferens elicited by alpha beta-methylene ATP (alpha beta meATP; mediated by P2X(1)-like receptors), contractions of the guinea-pig ileal longitudinal smooth muscle elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S mediated by P2Y(1)-like receptors), and the degradation of ATP by ecto-nucleotidases in folliculated Xenopus laevis oocytes. SB9 (0.1-10 microM) antagonized contractile responses produced by alpha beta meATP or ADP beta S in a concentration-dependent manner. Schild analysis yielded linear regression lines of unit slope, indicating competitive antagonism. From the rightward shifts of the agonist concentration-response curves pA(2) values of 6.05+/-0.13 (vas deferens) and 6.98+/-0.07 (ileum) were derived. In both preparations, SB9 behaved as a slow onset, slow offset antagonist. Incubation of three oocytes in the presence of ATP produced an increase in inorganic phosphate (P(i)) over a 30-min period, which amounted to 35.1+/-1.9 microM P(i) from 100 microM ATP. SB9 (10-1000 microM) reduced this degradation (pIC(50)=4.33+/-0.10). The results illustrate that SB9 is a high-affinity P2Y(1) receptor antagonist with a remarkable selectivity for P2Y(1) vs. P2X(1) receptors (about 10-fold) and ecto-nucleotidases (447-fold). These properties make it unique among the pyridoxal-5'-phosphate and suramin derivatives reported to date.

5'-Nucleotidase↗

PubMed2000

The novel pyridoxal-5'-phosphate derivative PPNDS potently antagonizes activation of P2X(1) receptors.

Pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonat e) (PPNDS) potently antagonized P2X(1) receptor-mediated responses in rat vas deferens (pK(B)=7.43) and Xenopus laevis oocytes (pIC(50)=7. 84). It showed lower (up to 20,000-fold) inhibitory potency on ecto-nucleotidase in Xenopus oocytes and on P2Y(1) receptors in guinea-pig ileum (pA(2)=6.13). PPNDS did not interact with alpha(1A)-adrenoceptors, adenosine A(1) and A(2B), histamine H(1) and muscarinic M(3) receptors. Thus, PPNDS is a novel, specific P2 receptor antagonist and represents the pyridoxal-5'-phosphate derivative with the highest potency at P2X(1) receptors.

Animals↗

PubMed2000

Muscarinic properties of compounds related to arecaidine propargyl ester.

A series of new analogues of the arecaidine propargyl ester (CAS 35516-99-5), APE, 1a) with alcohols consisting of 4 or 5 carbon atoms were investigated at muscarinic receptor subtypes. The muscarinic activity of the quaternary and tertiary salts of the APE-related compounds were assayed on the isolated guinea-pig ileum (M3 receptor subtype) and guinea-pig left atria (M2 receptor subtype) as well as on rabbit isolated vas deferens (M1 receptor subtype). The structural variations made in the APE molecule, replacing the triple bond in the ester side chain with structures such as double bond, an allene moiety, a single bond, a cyclopropyl group or two triple bonds should alter the selectivity and potency in favour of the M2 subtype. Enhanced, though modest, selectivity for M2 receptors was achieved with the 2-butynyl ester 2a. The other structural variations resulted in a loss of potency, but not necessarily of efficacy.

Animals↗

PubMed1995

The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist.

The present study was designed to determine to determine the in vitro affinity profile of (R)-(-)-dimethindene and (S)-(+)-dimethindene at muscarinic receptor subtypes using both functional and binding assays. In addition, the racemate was investigated in functional studies. The functional muscarinic receptors studied were putative M1 receptors in rabbit vas deferens and rat duodenum, M2 receptors in guinea-pig left atria and rabbit vas deferens, as well as M3 receptors in guinea-pig ileum and trachea. Furthermore, the histamine H1 antagonism by (R)-(-)- and (S)-(+)-dimethindene has been examined in guinea-pig ileum. Muscarinic binding selectivity was assessed in homogenates from human neuroblastoma NB-OF 1 cells (M1), rat heart (M2), pancreas (3) and striatum (M4). The results demonstrate that (S)-(+)-dimethindene is a potent M2-selective muscarinic receptor antagonist (pA2 = 7.86/7.74; pKi = 7.78) with lower affinities for the muscarinic M1 (pA2 = 6.83/6.36; pKi = 7.08), the M3 (pA2 = 6.92/6.96; pKi = 6.70) and the M4 receptors (pKi = 7.00), respectively. The (S)-(+)-enantiomer was more potent (up to 41-fold) than the (R)-(-)-enantiomer in all muscarinic assays. In contrast, the stereoselectivity was inverse at histamine H1 receptors, the (R)-(-)-enantiomer being the eutomer (pA2 = 9.42; pA2/(S)-isomer = 7.48). In conclusion, (S)-(+)-dimethindene is a useful tool to investigate muscarinic receptor heterogeneity. In addition, this lipophilic compound might become the starting point for the development of M2-selective muscarinic receptor antagonists useful as diagnostic tools for quantifying muscarinic M2 receptors in the central nervous system with positron emission tomography imaging, and to test the hypothesis that muscarinic M2 receptor antagonists show beneficial effects in the treatment of cognitive disorders.

Animals↗

PubMed1995

The design and pharmacology of novel selective muscarinic agonists and antagonists.

The muscarinic pharmacology of C1-methyl-substituted chiral compounds related to McN-A-343 and of (R)- and (S)-dimethindene has been studied. Among the McN-A-343 analogues, the (S)-enantiomers were more potent and had higher affinity than the (R)-isomers. The quaternary compound (S)-BN 228 was found to be the most potent M1-selective agonist known today (pEC50: M1/rabbit vas deferens = 7.83; M2/guinea-pig atria = 6.35; M3/guinea-pig ileum = 6.29). In both the atria and ileum the tertiary carbamate, (S)-4-F-MePyMcN, was a competitive antagonist (pA2 value = 7.39 and 6.82, respectively). In contrast, in rabbit vas deferens (S)-4-F-MePyMcN was a potent partial agonist (pEC50 = 7.22; apparent efficacy = 0.83). These results indicate that (S)-4-F-MePyMcN might be a useful tool to study M1 receptor-mediated effects involved in central cholinergic function. (S)-Dimethindene was a potent M2-selective antagonist (pA2 = 7.86/atria; pKi = 7.8/rat heart) with lower affinities for the M1 (pA2 = 6.36/rat duodenum; pKi = 7.1/NB-OK 1 cells), M3 (pA2 = 6.92/guinea-pig ileum; pKi = 6.7/rat pancreas) and M4 receptors (pKi = 7.0/rat striatum). It was more potent (up to 41-fold) than the (R)-isomer. In contrast, the stereoselectivity was inverse at ileal H1 receptors (pA2: (R)-isomer = 9.42; (S)-isomer = 7.48). Thus, (S)-dimethindene could be a valuable agent to test the hypothesis that M2 antagonists show beneficial effects in the treatment of cognitive disorders. It might also become the starting point for the development of diagnostic tools for quantifying M2 receptors in the CNS with PET imaging.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed1995

Children's judgements about psychological harm in social context.

72 children, ages 6 to 11 years, were presented with a series of stories involving psychological harm (name-calling) in a game context. Situations were presented in which intentions, consequences, and game context were varied, along with order of story presentation. Comparison between acts of physical and psychological harm were also conducted. Although responses in some conditions were influenced by order of presentation, age differences were found in children's evaluations of agents' actions and recipients' reactions for psychological harm in game contexts. Younger children were more likely to ignore intentions and consequences or the recipient's perspective and to focus on contextual features (e.g. game rules). Older children were more likely to base their evaluations on intentions, or both intentions and consequences, and to take into account the recipient's perspective. Game context interacted differentially with psychological and physical harm at all ages. Evaluations of acts of physical harm were more likely than acts of psychological harm to be transformed by game context.

Affect↗

PubMed1993

New functionally selective muscarinic agonists.

The muscarinic pharmacology of two novel agonists related to McN-A-343, 4-F-PyMcN and 4-F-PyMcN+, has been studied by the use of pharmacological and radioligand binding techniques. Both compounds were potent agonists at M1 receptors in rabbit vas deferens (pEC50 = 6.24 and 6.96) and rat duodenum (pEC50 = 5.47 and 6.38), but very weak partial agonists or competitive antagonists at guinea-pig cardiac M2 and ileal M3 receptors. There was no receptor reserve for 4-F-PyMcN in rabbit vas deferens, for which the potency (pEC50 = 6.24) and apparent affinity (pKA = 5.99 and 6.21) were similar. 4-F-PyMcN+ showed only limited binding selectivity between four muscarinic receptor binding assays with apparent affinity constants (pKi) of 5.8, 5.2, 5.6 and 5.7 for M1, M2, M3 and M4 muscarinic receptor subtypes. The two novel functionally M1-selective agonists may provide useful tools with which to study muscarinic receptor mechanisms. The non-quaternary compound, 4-F-PyMcN, might become a starting point for the development of drugs that selectively affect M1 receptors involved in central cholinergic function.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed1992

PPADS, a novel functionally selective antagonist of P2 purinoceptor-mediated responses.

We have characterized PPADS (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) as a novel antagonist which selectively blocks P2 purinoceptor-mediated responses in rabbit vas deferens at pre- and postjunctional sites. PPADS did not interact with alpha 1-adrenoceptors, muscarinic M2 and M3 receptors, histamine H1 and adenosine A1 receptors. Thus, PPADS is a novel and useful pharmacological tool to study co-transmission in tissues where ATP and co-existing neurotransmitters act in concert.

Adenosine Triphosphate↗

PubMed1992

Quantitative evaluation of sampling methods for Ixodes dammini and Amblyomma americanum (Acari: Ixodidae).

Three tick-sampling methods (dry ice-baited tick traps, cloth drags, and ambulatory human host) were evaluated to determine which technique yielded the greatest capture of host-seeking stages of Ixodes dammini Spielman, Clifford, Piesman & Corwin and Amblyomma americanum (L.). The most reliable method, catching more stages and significantly more numbers of I. dammini and A. americanum; was dry ice-baited tick traps. There were no significant differences between the drag and human-host methods for any stage of ticks (I. dammini and A. americanum) collected. The numbers of ticks caught during the study were 5,052 by dry ice-baited tick traps, 199 by cloth drags, and 89 by ambulatory human host.

Animals↗

PubMed1991

Judging social issues: difficulties, inconsistencies, and consistencies.

The three studies reported in this Monograph examine high school and college students' reasoning about the issues of abortion, homosexuality, pornography, and incest. The studies stemmed from previous research on reasoning in the "prototypical" moral, social conventional, and personal domains. We postulated that abortion, homosexuality, pornography, and incest are nonprototypical issues. We expected that reasoning about nonprototypical and prototypical issues would differ and that reasoning about nonprototypical issues would be inconsistent and involve ambiguities in informational assumptions. Two groups were preselected in Study 1, those who negatively and those who positively evaluated the nonprototypical issues. Assessments were made of criterion judgments (evaluations, rule contingency, and generalizability) and justifications regarding moral, personal, and nonprototypical issues. The groups differed in judgments about the nonprototypical issues but not the moral issues. Both groups gave noncontigent and generalized judgments about moral issues, with justifications of justice and rights. Subjects who evaluated nonprototypical acts negatively used varied and often inconsistent configurations of criterion judgments. Responses coded for general reasoning types often entailed juxtapositions of prescriptive judgments and assertions of personal choice. Subjects who evaluated nonprototypical acts positively judged that they should be legal and nongeneralized and gave justifications based on personal choice. Using similar procedures, Study 2 was conducted with practicing Catholics attending parochial high schools. The findings paralleled those of Study 1, including a split among subjects in their evaluations of the nonprototypical issues. The results suggested a bidirectional relation between individual judgments and group positions. The findings of Studies 1 and 2 suggested that variations in evaluations and judgments about the nonprototypical issues were associated with variations in ambiguously held informational assumptions. Study 3 examined the role of such informational assumptions. It was found that assumptions associated with judgments about abortion and homosexuality were ambiguous and inconsistently applied. Thus, we propose that ambiguity around assumptions is a central component of the nonprototypicality of these issues.

Abortion, Legal↗

PubMed1990

Competition between photobleaching and fluorescence increase of photosensitizing porphyrins and tetrasulphonated chloroaluminiumphthalocyanine.

The time-dependent fluorescence changes of photosensitizing porphyrins and tetrasulphonated chloroaluminiumphthalocyanine (A1C1SPc) were measured at different intracellular sites using video-enhanced microscopy and image processing. To obtain variations in intracellular fluorescence intensity, different radiant exposures of a Kr+ laser-pumped dye laser were delivered via a 600 microns plastic-clad silica fibre connected to the microscope. During irradiation, competition between photobleaching and fluorescence increase of the different dyes was observed. The porphyrins normally showed photobleaching, which was dependent on the sensitizer and its specific accumulation within the cell. Photobleaching was less pronounced for hydrophilic uroporphyrin than for more hydrophobic dyes. In contrast with an almost exponential decrease in porphyrin fluorescence with increasing light dose, the fluorescence intensity of A1C1SPc significantly increased at the beginning of irradiation, and could be correlated with intracellular deaggregation.

Animals↗