van Giersbergen PL


Full name : van Giersbergen Paul L

First name : Paul L

Mail : van Giersbergen Consulting, Wuenheim

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References (8)

Title : In vitro and in vivo characterization of MDL 105,212A, a nonpeptide NK-1\/NK-2 tachykinin receptor antagonist - Kudlacz_1996_J.Pharmacol.Exp.Ther_277_840
Author(s) : Kudlacz EM , Shatzer SA , Knippenberg RW , Logan DE , Poirot M , van Giersbergen PL , Burkholder TP
Ref : Journal of Pharmacology & Experimental Therapeutics , 277 :840 , 1996
Abstract : We have identified and characterized a novel, potent, nonselective tachykinin receptor antagonist, MDL 105,212A [(R)-1-[2-[3-(3,4- dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl] -ethyl]- 4-phenylpiperidine-4-carboxamide, hydrochloride]. The compound binds with low nanomolar affinity and species specificity to human NK-1 and NK-2 receptors as well as to guinea pig NK-3 receptors. In vitro functional assays are consistent with potent competitive antagonism of substance P-(SP) or neurokinin A-(NKA) induced [3H]-inositol phosphate accumulation in NK-1 or NK-2 monoreceptor cell lines with pA2 values of 8.19 and 8.67, respectively. Its ability to inhibit SP, NKA and capsaicin-mediated respiratory effects was examined in guinea pigs in vivo. MDL 105,212A attenuated SP-induced airway plasma protein extravasation (ED50 = 0.20 mg/kg, i.v.), NKA-induced respiratory collapse (ED50 = 5 mg/kg, i.v) and inhibited capsaicin-induced increases in pulmonary insufflation pressure (ED50 = 0.5 mg/kg, i.v.). Conscious guinea pigs responded to capsaicin aerosol exposure with dyspnea, coughs and gasps (significant respiratory events) and plasma protein extravasation. MDL 105,212A inhibited these responses in a dose-dependent manner after i.v. (ED50 = 5 mg/kg) or oral (ED50 = 50 mg/kg) administration. These data suggest that MDL 105,212A is a potent NK-1 and NK-2 receptor antagonist based on in vitro activity and its ability to inhibit SP and NKA mediated respiratory effects in vivo after exogenous administration or endogenous release and hence may be a useful therapeutic agent in neuroinflammatory disorders such as asthma in which a role for both tachykinins in the pathogenesis of the disease has been postulated.
ESTHER : Kudlacz_1996_J.Pharmacol.Exp.Ther_277_840
PubMedSearch : Kudlacz_1996_J.Pharmacol.Exp.Ther_277_840
PubMedID: 8627566

Title : Modulation of agonist binding by guanine nucleotides in CHO cells expressing muscarinic m1-m5 receptors - van Giersbergen_1995_Naunyn.Schmiedebergs.Arch.Pharmacol_352_166
Author(s) : van Giersbergen PL , Leppik R
Ref : Naunyn Schmiedebergs Arch Pharmacol , 352 :166 , 1995
Abstract : In membranes prepared from CHO-m2 cells, inhibition of [3H]-N-methylscopolamine ([3H]NMS) binding by several muscarinic agonists resulted in competition curves with Hill slopes significantly different from unity. Addition of 5'-guanylylimidodiphosphate (Gpp(NH)p) led to an increase in the IC50 value of the agonists with significant steepening of the inhibition curves. The shift in potency induced by Gpp(NH)p differed among the agonists with a rank order of oxotremorine-M = carbachol > oxotremorine > McN-A-343 = pilocarpine. In CHO-m4 membranes, Gpp(NH)p was less efficacious than in CHO-m2 membranes whereas no effect of the guanine nucleotide was found in membranes prepared from CHO-m1, -m3, and -m5 cells. No major differences in the effect of Gpp(NH)p among agonists were found in CHO-m4 cells. Atropine binding was not affected by the guanine nucleotide. Together, these results indicate that coupling of G-proteins to muscarinic receptors linked to inhibition of cyclic adenosine monophosphate (cAMP) (m2 and m4) but not of those linked to phosphoinositol turnover (m1, m3 and m5) can be perturbed by Gpp(NH)p. The differential effects observed with Gpp(NH)p between agonist binding to m2 and m4 receptors appear to be receptor-specific and may reflect differences in the G proteins activated by these receptors in CHO cells.
ESTHER : van Giersbergen_1995_Naunyn.Schmiedebergs.Arch.Pharmacol_352_166
PubMedSearch : van Giersbergen_1995_Naunyn.Schmiedebergs.Arch.Pharmacol_352_166
PubMedID: 7477439

Title : Differences in agonist potency ratios at human m1 muscarinic receptors expressed in A9L and CHO cells - Richards_1995_Life.Sci_57_397
Author(s) : Richards MH , van Giersbergen PL
Ref : Life Sciences , 57 :397 , 1995
Abstract : A9L mouse fibroblast and Chinese hamster ovary (CHO) cells appear to differ in their complement of guanine-nucleotide binding proteins (G proteins) and/or isoform of effectors that lead to inositol-monophosphate formation. The influence of these cellular components on receptor activation was examined by comparing agonist-induced inositol monophosphate formation via human muscarinic m1 receptors expressed in the two cell lines. The rank order of agonist potencies of five full agonists differed in the two cell lines. In addition, differences in agonist potency ratios for two of the five agonists (carbachol and methacholine) suggest that the agonists differ in their activation of m1 receptors and this is reflected in differences in G protein coupling. The results provide biological evidence that muscarinic agonists differentially activate m1 receptors and that, at least for the systems examined in this study, receptor-effector coupling in a given system may depend on the structure of the agonist.
ESTHER : Richards_1995_Life.Sci_57_397
PubMedSearch : Richards_1995_Life.Sci_57_397
PubMedID: 7603311

Title : Human muscarinic receptors expressed in A9L and CHO cells: activation by full and partial agonists - Richards_1995_Br.J.Pharmacol_114_1241
Author(s) : Richards MH , van Giersbergen PL
Ref : British Journal of Pharmacology , 114 :1241 , 1995
Abstract : 1. A comparative study of receptor activation by ten full and partial muscarinic agonists was undertaken on the five subtypes of human muscarinic receptors expressed at similar receptor densities in Chinese hamster ovary (CHO-K1) cells. In addition, m1, m2 and m3 receptors were expressed in mouse fibroblast A9L cells in order to compare the influences of cell type on agonist activation of these receptors. 2. Receptor-effector coupling efficiencies were greater in CHO than A9L cells and agonists displayed greater potencies and similar or greater intrinsic activities at CHOm1 and CHOm3 than A9Lm1 and A9Lm3 receptors. Although m2 receptor density was 6 fold higher in A9L than CHO cells, carbachol elicited significantly greater inhibition of adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation in CHOm2 cells. These data suggest that not only receptor density but receptor-effector coupling and/or coupling efficiencies play significant roles in agonist-induced responses. 3. In CHO cells, receptor-effector coupling efficiencies were m3 = m1 > m5. Although CHOm5 receptors were the least efficiently coupled, some partial agonists displayed higher intrinsic efficacies at m5 than m3 receptors suggesting that, in CHO cells, m5 and m3 receptors may activate different G proteins and/or effectors to stimulate inositol monophosphate (IP1) formation. 4. McN-A-343 was a functionally selective m4 agonist. It had little or no agonist activity at m3 receptors expressed in either A9L or CHO cells. The slopes of McN-A-343 concentration-response curves inCHOm2 cells were significantly lower than the slopes obtained with this compound in CHOm4 cells suggesting that the mode of activation by McN-A-343 differed between the two muscarinic receptors negatively coupled to adenylyl cyclase.5. Cloned receptors provide valuable tools for the study of agonist-receptor interaction and agonist receptor activation but caution should be applied in assuming that the results are valid for all cell types or for tissue-expressed receptors.
ESTHER : Richards_1995_Br.J.Pharmacol_114_1241
PubMedSearch : Richards_1995_Br.J.Pharmacol_114_1241
PubMedID: 7620715

Title : Poster: Synthesis and biological evaluation of MDL 74,019DG, a centrally active M1 versus M2 selective muscarinic receptor antagonist -
Author(s) : Van Hijfte L , Zerr V , Hibert M , Marciniak G , Moser P , Moran P , Richards MH , van Giersbergen PL
Ref : Life Sciences , 56(11-12) :1013 , 1995

Title : Muscarinic toxins from the black mamba Dendroaspis polylepis - Jolkkonen_1995_Eur.J.Biochem_234_579
Author(s) : Jolkkonen M , van Giersbergen PL , Hellman U , Wernstedt C , Oras A , Satyapan N , Adem A , Karlsson E
Ref : European Journal of Biochemistry , 234 :579 , 1995
Abstract : Three new toxins acting on muscarinic receptors were isolated from the venom of the black mamba Dendroaspis polylepis. They were called muscarinic toxins alpha, beta, and gamma (MT alpha, MT beta, and MT gamma). All of the toxins have four disulphide bonds and 65 or 66 amino acids. The sequences of MT alpha and MT beta were determined. The muscarinic toxins, of which about 12 have been isolated from venoms of green and black mambas, have 60-98% sequence identity with each other, and are similar to many (about 180) other snake venom components, such as alpha-neurotoxins, cardiotoxins, and fasciculins. In contrast to the alpha-neurotoxins, muscarinic toxins do not bind to nicotinic acetylcholine receptors. The binding constants of MT alpha and MT beta were determined for human muscarinic receptors of subtypes m1-m5 stably expressed in Chinese hamster ovary cells. The toxins are less selective than the earlier discovered muscarinic toxins from the green mamba Dendroaspis angusticeps. MT alpha and the muscarinic toxin MT4 from D. angusticeps differ only in a region of three amino acids (residues 31-33), which are Leu-Asn-His in MT alpha and Ile-Val-Pro in MT4. This difference causes a pronounced shift in subtype selectivity. MT alpha has high affinity to all subtypes, with Ki (inhibition constant) values of 23 nM (m1; pKi = 7.64 +/- 0.10), 44 nM (m2; pKi = 7.36 +/- 0.06), 3 nM (m3; pKi = 8.46 +/- 0.14), 5 nM (m4; pKi = 8.32 +/- 0.07), and 8 nM (m5; pKi = 8.09 +/- 0.07). MT4 has high affinity only to m1 (Ki = 62 nM) and m4 (87 nM) receptors, and low (Ki > 1 microM) affinity to m2, m3, and m5. The region at positions 31-33 evidently plays an important role in the toxin-receptor interaction. MT beta has low affinity for m1 and m2 receptors (Ki > 1 microM) and intermediate affinity for m3 (140 nM; pKi = 6.85 +/- 0.03), m4 (120 nM; pKi = 6.90 +/- 0.06), and m5 (350 nM; pKi = 6.46 +/- 0.01). The low affinity of MT beta may reflect a tendency for spontaneous inactivation.
ESTHER : Jolkkonen_1995_Eur.J.Biochem_234_579
PubMedSearch : Jolkkonen_1995_Eur.J.Biochem_234_579
PubMedID: 8536706

Title : A toxin from the green mamba Dendroaspis angusticeps: amino acid sequence and selectivity for muscarinic m4 receptors - Jolkkonen_1994_FEBS.Lett_352_91
Author(s) : Jolkkonen M , van Giersbergen PL , Hellman U , Wernstedt C , Karlsson E
Ref : FEBS Letters , 352 :91 , 1994
Abstract : Muscarinic toxin 3 (MT3) (65 amino acids, four disulphides, M(r) 7379) was isolated from the venom of the African snake Dendroaspis angusticeps (green mamba) and its amino acid sequence determined. Its ability to inhibit the binding of [3H]N-methylscopolamine ([3H]NMS) to Chinese hamster ovary cells stably expressing subtypes of muscarinic receptors was studied. MT3 displayed high affinity for the m4 receptor (pKi = 8.7 +/- 0.06), 40-fold lower affinity at ml receptors (pKi = 7.11 +/- 0.17) whereas no inhibition of [3H]NMS binding to m2, m3 and m5 receptors was observed at concentrations up to 1 microM. This makes MT3 the most selective m4 receptor ligand known to date.
ESTHER : Jolkkonen_1994_FEBS.Lett_352_91
PubMedSearch : Jolkkonen_1994_FEBS.Lett_352_91
PubMedID: 7925952

Title : Poster: Activation by full and partial agonists of M1 to M5 human muscarinic receptors expressed in A9L or CHO cells -
Author(s) : Richards MH , van Giersbergen PL , Jones CR
Ref : Life Sciences , 52(5-6) :576 , 1993