85 research outputs found
Morpholin-2-yl-phosphinic acids are potent GABAB receptor antagonists in rat brain
No full textThe pharmacological properties of morpholin-2-yl-phosphinic acids were evaluated on GABA(B) receptors. In rat neocortical slices maintained in Mg2+-free Krebs medium, baclofen, a GABA(B) receptor agonist, produced a concentration-dependent depression of the frequency of spontaneous discharges with an EC50 of 14 +/- 5.5 microM, which was antagonised reversibly by the morpholin-2-yl-phosphinic derivatives. The order of potency was 3-[(3S,6R)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl- morpholin-3-yl]benzoic acid (CGP 76290A) (pA2 = 7.1 +/- 0.05) > its enantiomer 3-[(3R,6S)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-++ +morpholin-3-yl]benzoic acid (CGP 76291A) (pA2 = 6.8 +/- 0.1) > cyclohexylmethyl-[(2R',5S')-5-(3-nitrophenyl)-morpholin-2-++ +ylmethyl]phosphinic acid (CGP 71978) (pA2 = 6.5 +/- 0.05) > cyclohexylmethyl-[(2R,5S)-5-phenyl-morpholin-2-ylmethyl++ +]phosphinic acid (CGP 71980) (pA2 = 6.3 +/- 0.15) > its enantiomer cyclohexylmethyl-[(2S,5R)-5-phenyl-morpholin-2-ylmethyl++ +]phosphinic acid (CGP 71979) (pA2 = 5.8 +/- 0.1). An open chain analogue of CGP 76290A, CGP 56999A (3-[1(R)-[(3-cyclohexylmethyl-hydroxyphosphinoyl)-2(S)-hydro xypropyl-amino]-ethyl]benzoic acid lithium salt) gave a pA2 of 6.6 +/- 0.2. In GABA(B) receptor binding assays, CGP 71982 (the racemic mixture of CGP 76290A and CGP 76291A), CGP 76290A, CGP 76291A, CGP 71978, CGP 71980 and CGP 71979 had IC50 values against [3H]CGP 27492 binding of 8, 1.85, 69, 124, 326 and 1460 nM, respectively. In electrically-evoked [3H]GABA release from rat cortical slices, CGP 71982, CGP 71978, CGP 71980 and its enantiomer CGP 71979, antagonised GABA(B) autoreceptors with EC150 values of 2.5, 33, 181 and 474 nM, respectively. These compounds form a novel class of potent GABA(B) receptor antagonists.Jennifer Ong, David I.B. Kerr, Helmut Bittiger, Peter C. Waldmeier, Peter A. Baumann, Nigel G. Cooke, Stuart J. Mickel, Wolfgang Froest
Pharmacological re-evaluation of a GABAB receptor antagonist CGP 47332A in rat brain
No full textIn rat neocortical slices maintained in Mg(2+)-free Krebs medium, the gamma-aminobutyric acid (GABA(B)) receptor agonist baclofen concentration-dependently depressed the frequency of spontaneous discharges (EC(50)=12 microM). This was reversibly antagonised by (R, S)-3-amino-2-hydroxy-propyl-P-n-butyl-phosphinic acid (CGP 47332A) (25, 100, 300 microM) which produced rightwards shifts of the baclofen concentration-response curves (pA(2) value=4.8+/-0.1). In electrically stimulated slices preloaded with [3H]GABA, CGP 47332A increased its release (EC(150)=100 microM) through antagonism of GABA(B) autoreceptors. Although CGP 47332A was some six times weaker on GABA(B) auto- than on heteroreceptors, yet its congener lacking the beta-hydroxy substituent displays equal potency in both binding (IC(50)=38 microM) and GABA(B) autoreceptor functional studies (EC(150)=38 microM) as previously reported [Froestl, W., Mickel, S.J. , Von Sprecher, G., Diel, P.J., Hall, R.G., Maier, L., Strub, D., Melillo, V., Baumann, P.A., Bernasconi, R., Gentsch, C., Hauser, K., Jaekel, J., Karlsson, G., Klebs, K., Maitre, L., Marescaux, C., Pozza, M.F., Schmutz, M., Steinmann, M.W., Van Riezen, H., Vassout, A., Mondadori, C., Olpe, H.R., Waldmeier, P.C., Bittiger, H., Phosphinic acid analogues of GABA: 2. Selective, orally active GABA(B) antagonists. J. Med. Chem. 38 (1995) 3313-3331.]
Comparative potencies of CGP 47654A and CGP 46165A as GABA (B) receptor antagonists in rat brain
No full textIn rat neocortical slices maintained in Mg2+-free Krebs medium, the gamma-aminobutyric acid (GABAB) receptor agonist baclofen concentration-dependently depressed the frequency of spontaneous discharges (EC50 = 6.1 microM). This was reversibly antagonised by 3-aminopropyl-(1,1-difluoro-n-butyl)-phosphinic acid (25, 100, 500 microM) (CGP 47654A) and 3-aminopropyl-P-(alpha-hydroxybenzyl)-phosphinic acid (CGP 46165A) (50, 100, 400 microM) which produced rightwards shifts of the baclofen concentration-response curves, with respective pA2 values of 4.9+/-0.2 and 4.6+/-0.15. Although relatively potent on GABAB heteroreceptors studied here, CGP 47654A and CGP 46165A were 5 and 50 times weaker, respectively, as GABAB autoreceptor antagonists [Froestl, W., Mickel, S.J., Von Sprecher, G., Diel, P.J., Hall, R.G., Maier, L., Strub, D., Melillo, V., Baumann, P.A., Bernasconi, R., Gentsch, C., Hauser, K., Jaekel, J., Karlsson, G., Klebs, K., Maitre, L., Marescaux, C., Pozza, M.F., Schmutz, M., Steinmann, M.W., Van Riezen, H., Vassout, A., Mondadori, C., Olpe, H.R., Waldmeier, P.C., Bittiger, H., 1995. Phosphinic acid analogues of GABA. 2. Selective, orally active GABAB antagonists. J. Med. Chem. 38: 3313-3331.], representing potentially useful ligands for differentiating GABA hetero- and autoreceptors
The sushi domains and their role in GABA(B) receptor compartmentalization
No full textGABAB receptors are G protein-coupled receptors fo
Forschung Frankfurt : das Wissenschaftsmagazin. 2012, Nr. 1
No full textSchwerpunkt: Gefäßforschung. Inhalt: Vorwort ... », Kompakt
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Vorschau und Impressum ...
Oxaprotiline and its enantiomers: do they open new avenues in the research on the mode of action of antidepressants?
No full textSurface modification with polymers using living radical polymerisation and click chemistry
No full textThin organic and polymer layers on solid substrates play a key role in many processes
aimed at modifying surface properties. Both "grafting to" and "grafting from"
methods have been used in this project to modify a variety of surfaces including
cellulose, resins and carbon nanotubes (CNT) with functional polymers. Living
radical polymerisation and Huisgen [2+3] cycloaddition (often termed "click"
reaction) were used to carry out these modifications.
Living radical polymerisation was first used to synthesize different α-functional
polymers and used for surface modification. For example, Living radical
polymerisations of methyl methacrylate and a fluorescent comonomer with 2-bromo-
2-methyl-propionic acid 3-azido-propyl ester and 2-bromo-2-methyl-hept-6-yn-3-one
as initiators have been successfully employed for the synthesis of fluorescently tagged
azide and alkyne terminated PMMA with molecular weight (Mn) close to that
predicted and polydispersity index (PDi) less than 1.20 and good first order kinetics
that would be expected for living radical polymerisation. Cotton and organic resin
surfaces have been functionalised with alkyne groups using simple condensation with
4-chlorocarbonyl-butyric acid prop-2-ynyl ester. The surfaces have been further
modifies using a Huisgen [2+3] cycloaddition (click) reaction of both polymeric and
small molecule azides. Different functional azides, namely mono azido-PEG and a
new fluorescent hostasol derivative have also been prepared and tested as model
substrates for cotton surface modification. This approach is shown to be very general
allowing soft and hard surfaces with different geometries to be modified. In particular
it is an excellent method to alter the nature of organic resins allowing the
incorporation of many different functionalities.
The covalent immobilization of a range of carbohydrate derivatives onto resin beads
was then carried out. Copper-catalysed Huisgen [2+3] cycloaddition was used to graft
mannose-containing azides to complementarily functionalised alkyne surfaces,
namely: a) Wang resin or b) "Rasta" particles consisting of a "clickable" alkyne
polymer loose outer shell and a Wang resin inner core. For the second approach,
Wang resin beads were first converted into immobilized ATRP initiators, and then
polymerisation of trimethylsilanyl-protected propargyl methacrylate followed by
deprotection with TBAF·3H2O afforded the desired polyalkyne clickable scaffold. An
appropriated α-mannopyranoside azide was then clicked onto it, to give a mannose
functionalized "Rasta" resin. The binding abilities of these D-mannose-modified
particles were then tested using fluorescein labelled Concanavalin A (Con A), a lectin
known for its ability of binding certain mannose-containing molecules. Our
preliminary results indicated that the novel glycohybrid materials presented in this
work are able to efficiently recognize mannose-binding model lectins such as Con A,
opening the way for their potential application in affinity chromatography, sensors
and other protein recognition/separation fields.
Other functional polymers with antibiotic or chiral properties were also grafted from
surfaces. Living radical polymerisation of poly(ethylene glycol) methyl ether
methacrylate (PEGMA) and a metronidazole monomer (MTD-MA) has been
successfully employed for the synthesis of antibiotic metronidazole containing
polymers with Mn close to that predicted, narrow polydispersity and good first order
kinetics that would be expected for living radical polymerisation. Using the
monomers PEGMA and MTD-MA, with preformed immobilized initiator on cotton,
surface initiated LRP was carried out to give cotton bearing antibiotic polymers.
Surface initiated living radical polymerisation of GMA was then successfully carried
out for the synthesis of PGMA containing bead base on Aquagel resin. The hydroxyl
groups of the PGMA moiety were then reacted with a single enantiomer (R)-(+)-1-
phenylethyl isocyanate (EtPhNCO). This demonstrates a convenient way of
immobilise enantiomer moiety onto resin surface and the resulting solid support may
be used as chiral stationary phases (CSP) for HPLC chromatography.
To modify CNTs with functional polymers not only increase the dispersability of the
CNTs, it has also enlarged the application areas of CNT’s due to the polymers' own
functional properties. MWCNTs were first converted to a solid support LRP initiator
by an esterification reaction and styrene was grafted from MWCNTs through surfaceinitiated
LRP, the PSt modified CNTs were then used to form isoporous membranes.
Similarly, Poly(amidoamine) (PAMAM) dendrons were covalently attached to
MWCNTs and dendron-MWCNT-Ag(0) hybrid materials were made afterwards
which occurred via Ag(I) coordination to the PAMAM dendron nitrogen donors,
followed by reduction with formaldehyde. Finally, noncovalent method was used to
make a thermo-sensitive water soluble CNTs. The homopolymerisations and
copolymerisation of poly(ethylene glycol) methyl ether methacrylate (PEGMA) and
di(ethylene glycol) methyl ether methacrylate (DEGMA) using a pyrene-containing
initiator and a Cu(0)/Me6-Tren catalyst system was investigated. The pyrenefunctionalised
polymers synthesised were then used to modify CNTs and thus thermosensitive
water-dispersible CNTs were made
Developmental changes of agonist affinity at GABABR1 receptor variants in rat brain
No full textRecently, two N-terminal splice variants of the metabotropic receptor for GABA (gamma-amino-butyric acid) were cloned. Here, we describe an antiserum that recognizes the two receptor variants. We demonstrate that these proteins are identical with GABAB receptors that are photoaffinity labeled with [125I]CGP71872 in rat brain. The C-terminal epitopes recognized by the antiserum are conserved in several vertebrate species but not in chicken. No hints for the existence of additional closely related receptor subtypes or variants are found in double-labeling experiments with antibody and photoaffinity ligand. Western blot analysis reveals widespread expression of the GABABR1 receptor proteins in rat brain with the highest level of expression at early postnatal stages. The binding affinity of the GABAB receptor agonist L-baclofen at native R1a and R1b variants is similar. In early postnatal development the affinity at R1a and R1b is 10-fold lower than in adult brain and gradually increases with aging
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