The Experts below are selected from a list of 153 Experts worldwide ranked by ideXlab platform
Klaus Starke - One of the best experts on this subject based on the ideXlab platform.
-
p2 receptor antagonists iv blockade of p2 receptor subtypes and ecto nucleotidases by compounds related to reactive blue 2
Naunyn-schmiedebergs Archives of Pharmacology, 1998Co-Authors: Florin Tuluc, Markus Glanzel, Ralph Bultmann, August W Frahm, Klaus StarkeAbstract:Effects of reactive blue 2 and twelve structurally related compounds were studied on contractions of the rat vas deferens elicited by alpha,beta-methylene ATP (alpha,beta-MeATP; mediated by P2X-receptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS; mediated by P2Y-receptors), and the degradation of ATP by rat vas deferens tissue. All compounds, except acid blue 41 and acid blue 129 (at up to 100 microM), shifted the concentration-response curve of alpha,beta-MeATP in the rat vas deferens to the right. Most increased, but uniblue A greatly decreased, the maximum of the curve. In the case of cibacron blue 3GA and reactive blue 19, of which three concentrations were tested, the Arunlakshana-Schild Regression was linear, and the slope did not differ from unity. The apparent Kd values of the effective substances ranged between 0.7 and 111 microM. Most compounds increased the contraction of the rat vas deferens elicited by high K+. In the guinea-pig taenia coli, all compounds, except uniblue A and reactive blue 19 (at up to 100 microM), shifted the concentration-response curve of ADPbetaS to the right in a parallel manner. In the case of acid blue 129 and acid blue 80, of which three concentrations were tested, the slope of the Arunlakshana-Schild Regression did not differ from unity. The apparent Kd values of the effective substances were between 0.7 and 69 microM. Most compounds also reduced the relaxation of the guinea-pig taenia coli elicited by noradrenaline. The removal of ATP from the medium by vas deferens tissue was decreased only by reactive blue 2, cibacron blue 3GA, uniblue A and reactive blue 19, with IC25% values between 17 and 62 microM. The structure-activity relationships for P2X- and P2Y-receptor blockade in this series are strikingly dissimilar. In reactive blue 2 and its isomers, for example, both the 1-amino-anthraquinone-2-sulphonate core and the 'side-chain' of the molecule are involved in P2X-receptor binding; P2Y-receptor affinity, in contrast, resides largely or totally in the anthraquinone core. The most promising antagonists are uniblue A which is P2X- versus P2Y-selective and acid blue 129 which is P2Y- versus P2X-selective, both with few, if any, non-P2-receptor effects at concentrations blocking the respective P2-subtype.
-
p2 purinoceptor antagonists ii blockade of p2 purinoceptor subtypes and ecto nucleotidases by compounds related to evans blue and trypan blue
Naunyn-schmiedebergs Archives of Pharmacology, 1996Co-Authors: Henning Wittenburg, Ralph Bultmann, Birgit Pause, Claudia Ganter, Gerhart Kurz, Klaus StarkeAbstract:Effects of Evans blue and four derivatives as well as of trypan blue and four derivatives, mostly smaller fragments but two compounds with an additional ethylene bridge in the center of the molecule, were studied on contractions of the rat vas deferens elicited by α,β-methylene ATP (α,β-McATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5′-O-(2-thiodiphosphate) (ADPβS; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. All compounds shifted the concentration-response curve of α,β-MeATP in the rat vas deferens to the right, and most compounds increased the maximum of the curve. Each member of the Evans blue series was similar in potency to the corresponding member of the trypan blue series. Where three concentrations were tested, the Arunlakshana-Schild Regression was linear, and the slope did not differ from 1. The apparent K d values were between 0.8 and 385 μM. In the guinea-pig taenia coli, only the members of the trypan blue group were relatively potent, shifting the concentration-response curve of ADPβS to the right in a surmountable manner. In 2 of 3 cases where three concentrations were tested, the slope of the Arunlakshana-Schild Regression was lower than 1. Apparent K d values in the trypan blue group were between 5.2 and 324 μM. The removal of ATP from the medium by vas deferens tissue was decreased mainly by the members of the Evans blue group, with IC25% values between 13 and 158 (in 1 case >1000) μM. The results indicate that the position of the sulphonate residues at the terminal naphthalene rings of these compounds hardly influences P2X purinoceptor affinity but greatly influences P2Y affinity and ecto-nucleotidase blockade. Among active compounds, apparent purinoceptor affinity and ecto-nucleotidase blockade increase with the size of the molecules up to Evans blue and trypan blue themselves; introduction of a central ethylene bridge does not result in a further gain in potency. NH01, the desmethyl derivative of Evans blue, seems to be interesting because it is the compound with the highest P2X- versus P2Y-selectivity presently available.
-
p2 purinoceptor antagonists iii blockade of p2 purinoceptor subtypes and ecto nucleotidases by compounds related to suramin
Naunyn-schmiedebergs Archives of Pharmacology, 1996Co-Authors: Ralph Bultmann, Henning Wittenburg, Birgit Pause, Gerhart Kurz, Peter Nickel, Klaus StarkeAbstract:Effects of suramin and five analogs or fragments of suramin were studied on contractions of the rat vas deferens elicited by alpha, beta-methylene ATP (alpha, beta-MeATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. One compound, NF023, differed from suramin by removal of two p-methylbenzamido groups, whereas another, BSt101, differed from NF023 by additional removal of the three sulphonate residues from one of the terminal naphthalene rings. The compounds all shifted the concentration-response curve of alpha, beta-MeATP in the rat vas deferens to the right and simultaneously increased the maximum of the curve. Where three concentrations were tested, the Arunlakshana-Schild Regression was linear, and the slope did not differ from 1. The apparent Kd values were between 1 and 3672 microM. In the guinea-pig taenia coli, the compounds shifted the concentration-response curve of ADP beta S to the right in a parallel manner, but in the one case where three concentrations were tested, the slope of the Arunlakshana-Schild Regression was lower than 1. Apparent Kd values were between 10 and 786 microM. The removal of ATP from the medium by vas deferens tissue was decreased only by suramin, NF023 and BSt101, with IC25% values between 170 and 590 microM.
Ralph Bultmann - One of the best experts on this subject based on the ideXlab platform.
-
p2 receptor antagonists iv blockade of p2 receptor subtypes and ecto nucleotidases by compounds related to reactive blue 2
Naunyn-schmiedebergs Archives of Pharmacology, 1998Co-Authors: Florin Tuluc, Markus Glanzel, Ralph Bultmann, August W Frahm, Klaus StarkeAbstract:Effects of reactive blue 2 and twelve structurally related compounds were studied on contractions of the rat vas deferens elicited by alpha,beta-methylene ATP (alpha,beta-MeATP; mediated by P2X-receptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS; mediated by P2Y-receptors), and the degradation of ATP by rat vas deferens tissue. All compounds, except acid blue 41 and acid blue 129 (at up to 100 microM), shifted the concentration-response curve of alpha,beta-MeATP in the rat vas deferens to the right. Most increased, but uniblue A greatly decreased, the maximum of the curve. In the case of cibacron blue 3GA and reactive blue 19, of which three concentrations were tested, the Arunlakshana-Schild Regression was linear, and the slope did not differ from unity. The apparent Kd values of the effective substances ranged between 0.7 and 111 microM. Most compounds increased the contraction of the rat vas deferens elicited by high K+. In the guinea-pig taenia coli, all compounds, except uniblue A and reactive blue 19 (at up to 100 microM), shifted the concentration-response curve of ADPbetaS to the right in a parallel manner. In the case of acid blue 129 and acid blue 80, of which three concentrations were tested, the slope of the Arunlakshana-Schild Regression did not differ from unity. The apparent Kd values of the effective substances were between 0.7 and 69 microM. Most compounds also reduced the relaxation of the guinea-pig taenia coli elicited by noradrenaline. The removal of ATP from the medium by vas deferens tissue was decreased only by reactive blue 2, cibacron blue 3GA, uniblue A and reactive blue 19, with IC25% values between 17 and 62 microM. The structure-activity relationships for P2X- and P2Y-receptor blockade in this series are strikingly dissimilar. In reactive blue 2 and its isomers, for example, both the 1-amino-anthraquinone-2-sulphonate core and the 'side-chain' of the molecule are involved in P2X-receptor binding; P2Y-receptor affinity, in contrast, resides largely or totally in the anthraquinone core. The most promising antagonists are uniblue A which is P2X- versus P2Y-selective and acid blue 129 which is P2Y- versus P2X-selective, both with few, if any, non-P2-receptor effects at concentrations blocking the respective P2-subtype.
-
p2 purinoceptor antagonists ii blockade of p2 purinoceptor subtypes and ecto nucleotidases by compounds related to evans blue and trypan blue
Naunyn-schmiedebergs Archives of Pharmacology, 1996Co-Authors: Henning Wittenburg, Ralph Bultmann, Birgit Pause, Claudia Ganter, Gerhart Kurz, Klaus StarkeAbstract:Effects of Evans blue and four derivatives as well as of trypan blue and four derivatives, mostly smaller fragments but two compounds with an additional ethylene bridge in the center of the molecule, were studied on contractions of the rat vas deferens elicited by α,β-methylene ATP (α,β-McATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5′-O-(2-thiodiphosphate) (ADPβS; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. All compounds shifted the concentration-response curve of α,β-MeATP in the rat vas deferens to the right, and most compounds increased the maximum of the curve. Each member of the Evans blue series was similar in potency to the corresponding member of the trypan blue series. Where three concentrations were tested, the Arunlakshana-Schild Regression was linear, and the slope did not differ from 1. The apparent K d values were between 0.8 and 385 μM. In the guinea-pig taenia coli, only the members of the trypan blue group were relatively potent, shifting the concentration-response curve of ADPβS to the right in a surmountable manner. In 2 of 3 cases where three concentrations were tested, the slope of the Arunlakshana-Schild Regression was lower than 1. Apparent K d values in the trypan blue group were between 5.2 and 324 μM. The removal of ATP from the medium by vas deferens tissue was decreased mainly by the members of the Evans blue group, with IC25% values between 13 and 158 (in 1 case >1000) μM. The results indicate that the position of the sulphonate residues at the terminal naphthalene rings of these compounds hardly influences P2X purinoceptor affinity but greatly influences P2Y affinity and ecto-nucleotidase blockade. Among active compounds, apparent purinoceptor affinity and ecto-nucleotidase blockade increase with the size of the molecules up to Evans blue and trypan blue themselves; introduction of a central ethylene bridge does not result in a further gain in potency. NH01, the desmethyl derivative of Evans blue, seems to be interesting because it is the compound with the highest P2X- versus P2Y-selectivity presently available.
-
p2 purinoceptor antagonists iii blockade of p2 purinoceptor subtypes and ecto nucleotidases by compounds related to suramin
Naunyn-schmiedebergs Archives of Pharmacology, 1996Co-Authors: Ralph Bultmann, Henning Wittenburg, Birgit Pause, Gerhart Kurz, Peter Nickel, Klaus StarkeAbstract:Effects of suramin and five analogs or fragments of suramin were studied on contractions of the rat vas deferens elicited by alpha, beta-methylene ATP (alpha, beta-MeATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. One compound, NF023, differed from suramin by removal of two p-methylbenzamido groups, whereas another, BSt101, differed from NF023 by additional removal of the three sulphonate residues from one of the terminal naphthalene rings. The compounds all shifted the concentration-response curve of alpha, beta-MeATP in the rat vas deferens to the right and simultaneously increased the maximum of the curve. Where three concentrations were tested, the Arunlakshana-Schild Regression was linear, and the slope did not differ from 1. The apparent Kd values were between 1 and 3672 microM. In the guinea-pig taenia coli, the compounds shifted the concentration-response curve of ADP beta S to the right in a parallel manner, but in the one case where three concentrations were tested, the slope of the Arunlakshana-Schild Regression was lower than 1. Apparent Kd values were between 10 and 786 microM. The removal of ATP from the medium by vas deferens tissue was decreased only by suramin, NF023 and BSt101, with IC25% values between 170 and 590 microM.
Anthony P D W Ford - One of the best experts on this subject based on the ideXlab platform.
-
α1l adrenoceptor mediation of smooth muscle contraction in rabbit bladder neck a model for lower urinary tract tissues of man
British Journal of Pharmacology, 1998Co-Authors: Shannon M Kava, D R Blue, R L Vimont, David E Clarke, Anthony P D W FordAbstract:1. The alpha1-adrenoceptor population mediating contractile responses to noradrenaline (NA) in smooth muscles of the bladder neck from rabbit (RBN) has been characterized by use of quantitative receptor pharmacology. 2. Experiments with several 'key' alpha1-adrenoceptor antagonists of varying subtype selectivities (RS-17053, BMY 7378, indoramin, 5-methylurapidil, prazosin, REC 15/2739, SNAP 5089, terazosin, WB 4101, tamsulosin, (+)-cyclazosin and RS-100329) were conducted. Schild Regression analyses yielded affinity (mean pKb) estimates of 7.1, 6.2, 8.6, 8.6, 8.4, 9.3, 7.0, 7.4, 8.9, 10.0, 7.1 and 9.3, respectively, although deviations from unit Schild Regression slope question the robustness of data for RS-17053 and SNAP 5089. 3. The nature of antagonism by these agents and the profile of affinity determinations generated together suggest that a single alpha1-adrenoceptor subtype mediates contractile responses of RBN to NA. Additional studies with phenylephrine indicated also an agonist-independence of this profile. Pharmacologically, this profile was reminiscent of that described as 'alpha1L'-adrenoceptor, which has been shown to mediate contractions of several tissues including lower urinary tract (LUT) tissues of man. Furthermore, a similarity was noticed between the 'alpha1L'-adrenoceptor described here in RBN and the rabbit and human cloned alpha1a-adrenoceptor (based on data from both whole cell radioligand binding at 37 degrees C and [3H]-inositol phosphates accumulation assays), characterizations of which have been published elsewhere. 4. In conclusion, the RBN appears to provide a predictive pharmacological assay for the study of NA-induced smooth muscle contraction in LUT tissues of man.
David G Lambert - One of the best experts on this subject based on the ideXlab platform.
-
ufp 101 a high affinity antagonist for the nociceptin orphanin fq receptor radioligand and gtpγ35s binding studies
Naunyn-schmiedebergs Archives of Pharmacology, 2003Co-Authors: John Mcdonald, Girolamo Calo, Remo Guerrini, David G LambertAbstract:Studies of the pharmacology of nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) have been hampered by the lack of a range of high potency antagonists. In this study we have examined the effects of a novel N/OFQ analogue [Nphe1,Arg14,Lys15]N/OFQ NH2 hereafter referred to as UFP-101. [3H]N/OFQ competition binding and GTPγ35S binding assays were performed using CHO cells expressing the human NOP receptor (CHOhNOP). UFP-101 (pKi of 10.14±0.09) and a range of NOP selective agonists displaced [3H]N/OFQ binding with the following rank order of affinity: [Arg14,Lys15]N/OFQ>[(pF)Phe4]N/OFQ(1–13)NH2>N/OFQ(1–13)NH2>UFP-101>N/OFQ>Ro64–6198>[Nphe1]N/OFQ(1–13)NH2. N/OFQ, N/OFQ(1–13)NH2, [(pF)Phe4]N/OFQ(1-13)NH2, [Arg14,Lys15]N/OFQ and Ro64–6198 also produced a concentration dependent (pEC50 values of 8.75±0.11, 9.28±0.15, 9.69±0.04, 9.12±0.11 and 8.09±0.07 respectively) and saturable stimulation of GTPγ35S binding and all were full agonists. UFP-101 did not stimulate GTPγ35S binding per se, but produced a concentration dependent and parallel rightward shift in the concentration response curves to all agonists. UFP-101 yielded pA2 values in the range 8.4–9.0. For comparison a pA2 for [Nphe1]N/OFQ(1–13)NH2 (the template for UFP-101) against N/OFQ of 7.33±0.08 was obtained. Slope factors for the Schild Regression lines were ~1 indicating competitivity. When UFP-101 is compared with its template molecule [Nphe1]N/OFQ(1–13)NH2, Arg14,Lys15 substitution produced ~1 log greater potency. We suggest that due to its high potency UFP-101 should prove a further useful tool in the evaluation of the N/OFQ-NOP receptor system.
Henning Wittenburg - One of the best experts on this subject based on the ideXlab platform.
-
p2 purinoceptor antagonists ii blockade of p2 purinoceptor subtypes and ecto nucleotidases by compounds related to evans blue and trypan blue
Naunyn-schmiedebergs Archives of Pharmacology, 1996Co-Authors: Henning Wittenburg, Ralph Bultmann, Birgit Pause, Claudia Ganter, Gerhart Kurz, Klaus StarkeAbstract:Effects of Evans blue and four derivatives as well as of trypan blue and four derivatives, mostly smaller fragments but two compounds with an additional ethylene bridge in the center of the molecule, were studied on contractions of the rat vas deferens elicited by α,β-methylene ATP (α,β-McATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5′-O-(2-thiodiphosphate) (ADPβS; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. All compounds shifted the concentration-response curve of α,β-MeATP in the rat vas deferens to the right, and most compounds increased the maximum of the curve. Each member of the Evans blue series was similar in potency to the corresponding member of the trypan blue series. Where three concentrations were tested, the Arunlakshana-Schild Regression was linear, and the slope did not differ from 1. The apparent K d values were between 0.8 and 385 μM. In the guinea-pig taenia coli, only the members of the trypan blue group were relatively potent, shifting the concentration-response curve of ADPβS to the right in a surmountable manner. In 2 of 3 cases where three concentrations were tested, the slope of the Arunlakshana-Schild Regression was lower than 1. Apparent K d values in the trypan blue group were between 5.2 and 324 μM. The removal of ATP from the medium by vas deferens tissue was decreased mainly by the members of the Evans blue group, with IC25% values between 13 and 158 (in 1 case >1000) μM. The results indicate that the position of the sulphonate residues at the terminal naphthalene rings of these compounds hardly influences P2X purinoceptor affinity but greatly influences P2Y affinity and ecto-nucleotidase blockade. Among active compounds, apparent purinoceptor affinity and ecto-nucleotidase blockade increase with the size of the molecules up to Evans blue and trypan blue themselves; introduction of a central ethylene bridge does not result in a further gain in potency. NH01, the desmethyl derivative of Evans blue, seems to be interesting because it is the compound with the highest P2X- versus P2Y-selectivity presently available.
-
p2 purinoceptor antagonists iii blockade of p2 purinoceptor subtypes and ecto nucleotidases by compounds related to suramin
Naunyn-schmiedebergs Archives of Pharmacology, 1996Co-Authors: Ralph Bultmann, Henning Wittenburg, Birgit Pause, Gerhart Kurz, Peter Nickel, Klaus StarkeAbstract:Effects of suramin and five analogs or fragments of suramin were studied on contractions of the rat vas deferens elicited by alpha, beta-methylene ATP (alpha, beta-MeATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. One compound, NF023, differed from suramin by removal of two p-methylbenzamido groups, whereas another, BSt101, differed from NF023 by additional removal of the three sulphonate residues from one of the terminal naphthalene rings. The compounds all shifted the concentration-response curve of alpha, beta-MeATP in the rat vas deferens to the right and simultaneously increased the maximum of the curve. Where three concentrations were tested, the Arunlakshana-Schild Regression was linear, and the slope did not differ from 1. The apparent Kd values were between 1 and 3672 microM. In the guinea-pig taenia coli, the compounds shifted the concentration-response curve of ADP beta S to the right in a parallel manner, but in the one case where three concentrations were tested, the slope of the Arunlakshana-Schild Regression was lower than 1. Apparent Kd values were between 10 and 786 microM. The removal of ATP from the medium by vas deferens tissue was decreased only by suramin, NF023 and BSt101, with IC25% values between 170 and 590 microM.
