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C G Wermuth

Publications and source records attributed to C G Wermuth.

At least 55 records · Page 3Linked to original sources
PubMed1985

gamma-Hydroxybutyrate uptake by rat brain striatal slices.

gamma-Hydroxybutyrate uptake by rat brain striatal slices was studied. The uptake was saturable with a Km of 702 +/- 107.10(-6) M. gamma-Hydroxybutyrate uptake was sodium dependent and inhibited by the omission of potassium. In addition, the effect of ouabain suggests that the transport is dependent on a cation gradient. Several analogues of gamma-hydroxybutyrate inhibit the transport system. GABA has no significant effect. This energy and cation dependent transport system is in favor of a transmitter or modulator role of gamma-hydroxybutyrate in the rat brain striatum.

Animals↗
PubMed1985

Synthesis and activity of 5-(aminomethylene)-1,3-cyclohexanediones: enolic analogues of gamma-aminobutyric acid.

Eight 1,3-cyclohexanediones with an aminoalkyl side chain in the 5-position were synthesized as rigid enolic analogues of GABA (gamma-aminobutyric acid). Biochemical investigations about their abilities to displace [3H]GABA and [3H]baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid] in binding studies or to inhibit the high-affinity sodium-dependent GABA uptake showed that these compounds were generally devoid of affinity for the two GABA receptors and for the GABA carrier. Only compound 1 exhibited a weak affinity in the GABA-A binding experiments (IC50 = 6.5 X 10(-5) M). Graphic computer modeling was applied in an attempt to explain this activity in comparison to some reference GABA agonists. Electrophysiological studies on dorsal root ganglia (DRG) also excluded agonistic or antagonistic properties on GABA-A or GABA-B receptor models but pointed out an atypical prolongation of Ca2+-dependent action potential for compound 1.

Action Potentials↗
PubMed1985

An arylaminopyridazine derivative of gamma-aminobutyric acid (GABA) is a selective and competitive antagonist at the GABAA receptor site.

In view of finding a new gamma-aminobutyric acid (GABA) receptor ligand we synthesized an arylaminopyridazine derivative of GABA, SR 95103 [2-(carboxy-3'-propyl)-3-amino-4-methyl-6-phenylpyridazinium chloride]. SR 95103 displaced [3H]GABA from rat brain membranes with an apparent Ki of 2.2 microM and a Hill number near 1.0. SR 95103 (1-100 microM) antagonized the GABA-mediated enhancement of [3H]diazepam binding in a concentration-dependent manner without affecting [3H]diazepam binding per se. SR 95103 competitively antagonized GABA-induced membrane depolarization in rat spinal ganglia. In all these experiments, the potency of SR 95103 was close to that of bicuculline. SR 95103 (100 microM) did not interact with a variety of central receptors--in particular the GABAB, the strychnine, and the glutamate receptors--did not inhibit Na+-dependent synaptosomal GABA uptake, and did not affect GABA-transaminase and glutamic acid decarboxylase activities. Intraperitoneally administered SR 95103 elicited clonicotonic seizures in mice (ED50 = 180 mg/kg). On the basis of these results it is postulated that St 95103 is a competitive antagonist of GABA at the GABAA receptor site. In addition to being an interesting lead structure for the search of GABA ligands, SR 95103 could also be a useful tool to investigate GABA receptor subtypes because it is freely soluble in water and chemically stable.

Animals↗
PubMed1983

Tissue and substrate specificity of inhibition by alkoxy-aryl-lactams of platelet and arterial smooth muscle cyclic nucleotide phosphodiesterases relationship to pharmacological activity.

Alkoxy-aryl-lactams (cilostamide, AAL 05, ZK 62 711, Ro 20-1724) inhibit differently cAMP or cGMP phosphodiesterases from blood platelets or vascular smooth muscle. Cilostamide (IC50 0.23 microM) and AAL 05 (IC50 0.15 microM) are 100 times more potent towards platelet cAMP phosphodiesterase whereas ZK 62 711 (IC50 2 microM) and Ro 20-1724 (IC50 33 microM) inhibit more selectively the enzyme from aorta. The substrate specificity of the inhibitors is different in the two tissues: ZK 62 711 and cilostamide are respectively 345 and 290 times more potent as inhibitor of cAMP than cGMP phosphodiesterase from vascular smooth muscle (ZK 62 711) or platelets (cilostamide). M + B 22,948 selectively inhibits cGMP phosphodiesterase with an IC50 of 9 or 24 microM on platelet or aorta enzyme, respectively. In general, the potencies of spasmolytic and platelet inhibitor effects vary from one drug to the other with the potency of inhibition of phosphodiesterase from the corresponding tissue. These data suggest that phosphodiesterases from platelets are different from those of arterial smooth muscle.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1982

High affinity binding sites for gamma-hydroxybutyric acid in rat brain.

The existence of a specific synthesizing enzyme for gamma-hydroxybutyric acid in rat brain has recently been reported. Here, for the first time, we demonstrate the presence of a high affinity, apparently specific binding site for this compound in the same tissue. This binding does not require Na+ and takes place optimally at pH 5.5. The bound gamma-hydroxybutyric acid is not displacable by GABA or baclofen. We report here on some structurally related compounds of GHB with a similar or better binding capacity than GHB itself. The number of binding sites increases with age up to adulthood and differs depending on the brain region. In primary tissue cultures of pure chicken neurones and glia, gamma-hydroxybutyric acid binding occurs exclusively in the neuronal preparations.

Animals↗
PubMed1982

A high-affinity, Na+-dependent uptake system for gamma-hydroxybutyrate in membrane vesicles prepared from rat brain.

gamma-Hydroxybutyrate (GHB) is a compared with numerous neuropharmacological properties. The discovery of its biosynthetic system, together with its endogenous repartition, have prompted its possible implication in neurotransmission. The role is also supported by the existence, reported here, of a high-affinity uptake system for GHB (Km = 46.4 microM) in both purified brain plasma membrane vesicles and in the crude mitochondrial fraction. GHB uptake is dependent on a Na+ gradient but is independent of the membrane electrical potential. Cl- and K+ can also modulate the uptake. As an approach to determine the conformation required for GHB uptake, a series of related compounds, including aryl- or alkyl- derivatives, has been examined for ability to inhibit GHB uptake. The regional distribution of uptake is also indicative of its possible physiological role, since in striatum, an area where GHB has a known pharmacological effect on dopaminergic neurons, this uptake activity is the highest.

Animals↗
PubMed1980

Studies on some para-substituted clonidine derivatives that exhibit an alpha-adrenoceptor stimulant activity.

1 alpha-Adrenoceptor stimulant activity was determined for noradrenaline (NA), clonidine and a series of para-substituted derivatives of clonidine on rat aortic strips, a rat brain synaptosome preparation, and anaesthetized pithed rats. The effects on the blood pressure of intraventricular (i.c.v.) injections of para-aminoclonidine were also determined in anaesthetized rats. 2 Para-substituted derivatives of clonidine (amino-, diethylamino-, ethylamino-, acetamido-, bromoacetamido-, N-chloroethyl-N-methyl-amino and N-beta-chloroethyl-N-methylaminomethyl-) retain alpha-adrenoceptor stimulant activity. 3 pD2 values determined on rat aortic strips were 11.2, 7.67 and 9.05 respectively for para-aminoclonidine, clonidine and noradrenaline. The Ki values of these agents, determined on a rat brain synaptosomal preparation with a radioreceptor assay using [3H]-clonidine as ligand, were 1.3, 8.0 and 23 nM respectively for para-aminoclonidine, clonidine and NA. When given by i.c.v. injection in rats, para-aminoclonidine lowered the blood pressure. 4 N-beta-chloroethyl-N-methylaminomethylclonidine is an alkylating agent with an unusual agonist activity. It elicits contractions of the rat aorta that persist despite repeated washing. 5 alpha-Adrenoceptor affinities are discussed in relation to their structural features.

Adrenergic alpha-Agonists↗
PubMed1978

[Pharmacological study of para-aminoclonidine, an alpha sympathomimetic].

Para-aminoclonidine is a more potent alpha-adrenergic agent than clonidine; in vitro on Rat aorta it is 150 times more active than NE, in vivo on pithed Rat it is still twice as active. The hypotensive action of paraaminoclondine is only manifested when given intraventricularly. In the conscious Rat, it has a diuretic action when given per os. Following IV injection in the anaesthetized Dog, the para-aminoclonidine induces an essentially hydric diuresis which is independet of its hypertensive action.

Adrenergic alpha-Agonists↗
PubMed1977

Synthesis and beta-adrenergic blocking activity of a novel class of aromatic oxime ethers.

A new series of beta-adrenergic blocking amines containing an oximino-propanolic chain linked to an aromatic nucleus was synthesized. Most of the derivatives are characterized by beta2-selectivity. The structure-activity relationship are discussed. One of the compounds, selected for further studies, was more active on the trachea than on the atria of guinea pig, 155 times in vitro and 26 times in vivo. In comparison, butoxamine's beta2-selectivity is 13 in vitro and only 2 in vivo. With a series of 30 acetophenone oxime derivatives, no quantitative structure-activity relationships could be detected.

Adrenergic beta-Antagonists↗
PubMed1977

A potent new beta2-adrenoceptor blocking agent.

1 (t-Butyl-amino-3-ol-2-propyl) oximino-9 fluorene is a new beta2-adrenoceptor blocking agent with a pA2 of 9.23+/-0.25 on isolated trachea. 2 It provokes hypertension in normotensive rats and does not prevent arterial hypertension in SHR rats, although it does prevent the renin secretion normally induced by isoprenaline infusion.

Adrenergic beta-Antagonists↗
PubMed1976

Immunochemical study of the peptidoglycan of gram-negative bacteria.

The specificity of antibodies directed against the peptidoglycan of gram-negative bacteria was studied. The peptidoglycans of Proteus vulgaris, Escherichia coli, Moraxella glucidolytica, Neisseria perflava, give identical precipitin reactions. By means of inhibition studies with various peptidoglycan subunits and synthetic peptides, it was shown that the antibodies are essentially directed against the peptide moiety of the peptidoglycan: L-Ala-D-Glu (L)-mesoA2pm-(L)-D-Ala, that the peptide reacts better with antibodies when it is not cross-linked, and that the C-terminal portion-meso-A2pm-D-Ala of the peptide is immunodominant. These results explain the immunological identity of the peptidoglycans of gram-negative bacteria, which possess the same peptide subunit. Only weak cross-reactivity was observed with the peptidoglycans of gram-positive bacteria (Streptococcus faecium, Micrococcus lysodeikticus, Corynebacterium poinsettiae) where meso-diaminopimelic acid is replaced by L-lysine or L-homoserine. However, the peptidoglycan of Bacillus megaterium which possesses the same peptide subunit as gram-negative bacteria, gives only a reaction of partial identity with these bacteria. This result suggests the presence on the peptidoglycan of gram-negative bacteria, of other undefined antigenic determinants.

Bacteria↗
PubMed1976

Clonidine and related analogues. Quantitative correlations.

Twenty-two structural derivatives of clonidine [2-(2,6-dichlorophenylimino)imidazolidine] have been synthesized and their main physicochemical parameters (log P, deltaRM, pKa) determined. Quantitative correlations between the peripheral alpha-mimetic action (pithed rats) and physicochemical parameters pointed out the critical role of the steric effect in the ortho positions. On the other hand, attempted quantitative correlations between physicochemical parameters and central hypotensive activity were unsuccessful. These results are discussed in the light of the postulated mechanism of action of clonidine.

Adrenergic alpha-Agonists↗