GABAB receptor antagonism by 7-MBFG, a benzo[b]furan analogue of baclofen, in central and peripheral tissues

1998 ◽  
Vol 76 (7-8) ◽  
pp. 798-801
Author(s):  
Jennifer Ong ◽  
David I Kerr ◽  
M'Hammed Ansar ◽  
Claude Vaccher ◽  
Pascal Berthelot
Keyword(s):  
Guinea Pig ◽  
Response Curve ◽  
Gabab Receptor ◽  
Guinea Pig Ileum ◽  
Butanoic Acid ◽  
Peripheral Tissues ◽  
Aromatic Character ◽  
Rat Neocortex ◽  
The Right ◽  
Concentration Response Curve

(R,S)-4-Amino-3-(7-methylbenzo[b]furan-2-yl)-butanoic acid (7-MBFG), a new benzofuran analogue of the GABAB receptor agonist baclofen, has been evaluated for pharmacological activity on GABAB receptors in the guinea-pig isolated ileum and rat neocortical slices. 7-MBFG (300 and 500 µM) reversibly antagonized the (R,S)-baclofen induced depression of cholinergic twitch contractions in the guinea-pig ileum and shifted the concentration-response curve for baclofen to the right, in a parallel manner, giving an apparent pA2 value of 3.7 ± 0.3. Likewise, 7-MBFG (300 and 500 µM) reversibly blocked the baclofen-induced suppression of spontaneous discharges, in rat neocortical slices maintained in Mg2+-free Krebs medium, and caused a rightward, parallel shift of the baclofen concentration-response curve, giving an apparent pA2 value of 4.1 ± 0.1. The compound 7-MBFG belongs to a novel, new class of antagonist at central and peripheral GABAB receptors, in which the antagonist properties reside in the pseudo-aromatic character of their 3-benzo[b]furan-2-yl substituents, and might provide useful leads for further development of GABAB receptor ligands.Key words: (R,S)-baclofen, 4-amino-3-(7-methylbenzo[b]furan-2-yl)-butanoic acid, GABAB receptor antagonist, rat neocortex, guinea-pig ileum.

Potential GABAB Receptor Antagonists. VII. The Synthesis of 2-(4-Chlorophenyl)-3-nitropropan-1-amine and Related Analogs of Baclofen

1994 ◽  
Vol 47 (8) ◽  
pp. 1441 ◽  
Author(s):  
G Abbenante ◽  
R Hughes ◽  
RH Prager
Keyword(s):  
Double Bond ◽  
Guinea Pig ◽  
Sodium Borohydride ◽  
Nitrous Acid ◽  
Gabab Receptor ◽  
Guinea Pig Ileum ◽  
Efficient Route ◽  
Gabab Receptor Antagonists ◽  
Curtius Degradation ◽  
The Michael Addition

3-Nitro-2-phenylpropan-1-amine and 2-(4-chloropenyl)-3-nitropropan-1-amine have been synthesized by the addition of nitrous acid to the corresponding trifluoroacetylaminomethylstyrenes followed by reduction of the double bond with sodium borohydride. A more general and efficient route involves the Michael addition of nitroalkane anions to methyl cinnamates followed by Curtius degradation of the corresponding acids. 2-(4-Chlorophenyl)-3-nitropropan-1-amine is a specific agonist of GABA and the GABAB receptor, with about half the activity of racemic baclofen at the isolated guinea pig ileum. Methylation or dimethylation at C3 decreases activity markedly.

scholarly journals GABAA and GABAB receptor-mediated effects in guinea-pig ileum

1983 ◽  
Vol 78 (3) ◽  
pp. 469-478 ◽  
Author(s):  
A. Giotti ◽  
S. Luzzi ◽  
S. Spagnesi ◽  
Lucilla Zilletti
Keyword(s):  
Guinea Pig ◽  
Gabab Receptor ◽  
Guinea Pig Ileum ◽  
Mediated Effects

GABAB receptor antagonism by resolved (R)-saclofen in the guinea-pig ileum

1996 ◽  
Vol 308 (3) ◽  
pp. R1-R2 ◽  
Author(s):  
David I.B. Kerr ◽  
Jennifer Ong ◽  
Claude Vaccher ◽  
Pascal Berthelot ◽  
Nathalie Flouquet ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Gabab Receptor ◽  
Guinea Pig Ileum ◽  
Receptor Antagonism

Blockade of histamine-induced contractions of guinea pig ileum by β-haloalkylamines

1976 ◽  
Vol 54 (3) ◽  
pp. 386-392 ◽  
Author(s):  
T. P. Kenakin ◽  
D. A. Cook
Keyword(s):  
Guinea Pig ◽  
Dose Response ◽  
Response Curve ◽  
Longitudinal Muscle ◽  
Sodium Thiosulfate ◽  
Dose Response Curve ◽  
Maximum Response ◽  
Guinea Pig Ileum ◽  
Parallel Shift ◽  
Higher Doses

In the longitudinal muscle strip of guinea pig ileum phenoxybenzamine (POB) produces a maximum parallel shift of 0.7 log units in the dose–response curve to histamine. In the presence of sodium thiosulfate in the wash fluid the parallel shift with retention of maximum response increases to about 2 log units, and a similar value is obtained for N-ethyl-N-(2-bromoethyl)-1′-naphthylamine. The agent N-ethyl-N-(2-chloroethyl)benzylamine produces a significantly smaller shift of dose–response curve of 1.53 log units before the maximum response becomes depressed. The receptor-specific depression of maximum response produced by higher doses of POB is reversed by sodium thiosulfate and by bovine serum albumin, while the parallel shift in dose–response curve is unaffected by both treatments. These findings may be explained by a hypothesis involving interaction of 2-haloalkylamines at two sites.

Existence of two types of postjunctional α-adrenoceptors in the isolated canine internal carotid artery

1988 ◽  
Vol 66 (5) ◽  
pp. 655-659 ◽  
Author(s):  
Yasuaki Kawai ◽  
Shigeaki Kobayashi ◽  
Toshio Ohhashi
Keyword(s):  
Response Curve ◽  
Carotid Arteries ◽  
Internal Carotid ◽  
The Other ◽  
Low Concentrations ◽  
Selective Agonists ◽  
High Concentrations ◽  
The Right ◽  
Internal Carotid Arteries ◽  
Concentration Response Curve

The pharmacological characteristics of postjunctional α-adrenoceptors in isolated canine internal carotid arteries were investigated by the use of selective agonists and antagonists for α1 and α2-adrenoceptors. Norepinephrine, phenylephrine, and xylazine caused concentration-dependent contractions in the helical strips. The contraction induced by 10−4 M xylazine was significantly smaller than that produced by 10−4 M norepinephrine or 10−4 M phenylephrine. The contraction induced by 10−4 M phenylephrine was almost the same value as that induced by 10−4 M norepinephrine. Phentolamine (10−8 and 10−7 M) caused a parallel shift to the right of the concentration–response curve to norepinephrine. The contractile responses to low concentrations of norepinephrine were significantly suppressed by pretreatment with an α2-antagonist such as yohimbine (10−9 and 10−8 M) or DG 5128(10−7 and 10−6 M). On the other hand, the responses to higher concentrations of norepinephrine were mainly reduced by low concentrations of an α1-antagonist, prazosin (3 × 10−10 and 3 × 10−9 M). These results suggest that both α1- and α2-adrenoceptors are located on the plasma membrane of smooth muscle cells in canine internal carotid arteries and that the norepinephrine-induced contractions at low and high concentrations are mainly mediated by activation of α2- and α1-adrenoceptors, respectively.

EFFECT OF ANGIOTENSIN ON THE RELEASE OF ACETYLCHOLINE FROM PREGANGLIONIC AND POSTGANGLIONIC NERVE ENDINGS

1967 ◽  
Vol 45 (2) ◽  
pp. 313-317 ◽  
Author(s):  
J. -C. Panisset
Keyword(s):  
Guinea Pig ◽  
Fold Increase ◽  
Guinea Pig Ileum ◽  
Cholinergic Mechanism ◽  
Cervical Ganglion ◽  
Release Of Acetylcholine ◽  
Stimulation Period ◽  
Effective Doses ◽  
The Right ◽  
Postganglionic Nerve

Angiotensin is known to stimulate the synaptic transmission of the cat superior ganglion and the contraction of the isolated guinea pig ileum; to determine whether these effects could be mediated by a cholinergic mechanism, both preparations were tested for the possible release of acetylcholine by angiotensin. The right cervical ganglion of 12 anesthetized cats was perfused with heparinized cat plasma, and the preganglionic sympathetic trunk was electrically stimulated supramaximally at 10-min intervals. After each stimulation, the acetylcholine content of the effluent was determined by bioassay. Angiotensin, injected intraarterially toward the ganglion in amounts ranging from 0.1 to 100 ng immediately before a stimulation period induced a 30 to 50% increase in acetylcholine output. Most effective doses ranged from 0.5 to 20 ng. Comparable experiments were carried out on coaxially stimulated strips of guinea pig ileum in Krebs solution. The addition of angiotensin, 1 ng/ml, was followed by a 4.3-fold increase in acetylcholine release during the period of contractile stimulation. From these two sets of data, it is concluded that angiotensin exerts a cholinergic action at the preganglionic level in the ganglion and at a postganglionic site in the ileum.

scholarly journals 3-Aminopropylphosphinic acid-a potent, selective GABAB receptor agonist in the guinea-pig ileum and rat anococcygeus muscle

1989 ◽  
Vol 97 (4) ◽  
pp. 1292-1296 ◽  
Author(s):  
Judith M. Hills ◽  
Rhona A. Dingsdale ◽  
Michael E. Parsons ◽  
Roland E. Dolle ◽  
William Howson
Keyword(s):  
Guinea Pig ◽  
Receptor Agonist ◽  
Gabab Receptor ◽  
Guinea Pig Ileum ◽  
Anococcygeus Muscle ◽  
Rat Anococcygeus Muscle

NiCl2 and Amiloride Induce Spreading Depression in Guinea Pig Hippocampal Slices

Cephalalgia ◽  
2000 ◽  
Vol 20 (8) ◽  
pp. 740-747 ◽  
Author(s):  
A Gorji ◽  
D Scheller ◽  
F Tegtmeier ◽  
R Köhling ◽  
H Straub ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Calcium Channel Blockers ◽  
Response Curve ◽  
Spreading Depression ◽  
Hippocampal Slices ◽  
Nmda Antagonist ◽  
Calcium Oscillations ◽  
Channel Blockers ◽  
Dc Potential ◽  
Concentration Response Curve

Spreading depressions (SD) occur in association with ischaemia, epilepsy and migraine. Intracellular calcium oscillations have been suggested to be involved in the generation and propagation of SD. The present study was performed to study the mechanism of conditioning guinea pig hippocampal slices by the T-type calcium channel blockers NiCl2 and amiloride. SD-like fluctuations of DC potential were recorded by inserting microelectrodes into the CA1 and CA3 regions. The SD occurrence was significantly greater with 10 µmol/ l NiCl2 as well as with 25 and 50 µmol/ l amiloride than with other concentrations of these substances. The concentration response curve was inversely U-shaped with the maximum repetition rates of SDs being achieved at 10 µmol/ l NiCl2 as well as at 25 and 50 µmol/ l amiloride. SD occurrence could be completely blocked by the NMDA antagonist APV (10 µmol/ l) in all cases. These data demonstrate that modulation of the Ca2+ dynamics conditioned guinea pig hippocampal slices and increased their susceptibility to generate SD.

Specific desensitization (tachyphylaxis) of the guinea pig ileum to angiotensin II

1977 ◽  
Vol 232 (2) ◽  
pp. H223-H230 ◽  
Author(s):  
T. B. Paiva ◽  
G. B. Mendes ◽  
A. C. Paiva
Keyword(s):  
Angiotensin Ii ◽  
Guinea Pig ◽  
Calcium Binding ◽  
Tight Binding ◽  
Guinea Pig Ileum ◽  
Response Curves ◽  
A Value ◽  
Zero Order Kinetics ◽  
Rate Of Recovery ◽  
The Right

Tachyphylaxis to [Ile5]angiotensin II (angiotensin) in the isolated guinea pig ileum was found to be more severe when the Ca2+ concentration or the temperature of the medium were lowered, or when glucose was absent. Incubation with indomethacin or prostaglandin E2 did not affect the onset of tachyphylaxis or recovery from the tachyphylactic state. The angiotensin dose-response curves of tachyphylactic organs were shifted to the right, and the maximum responses were depressed in proportion to the conditioning doses of the hormone. The recovery from tachyphylaxis followed zero-order kinetics and was not affected by Ca2+ concentration or pH. The temperature dependence of the rate of recovery yielded a value of 14.6 kcal/mol for the activation energy in the physiological temperature range. It is concluded that tachyphylaxis results from the tight binding of angiotensin to superficial calcium-binding sites in the smooth muscle cell membrane. Recovery from tachyphylaxis appears to involve displacement of angiotensin by calcium in a process that is dependent on active transport.

Glycoprotein VI–mediated platelet fibrinogen receptor activation occurs through calcium-sensitive and PKC-sensitive pathways without a requirement for secreted ADP

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3228-3234 ◽  
Author(s):  
Todd M. Quinton ◽  
Fatih Ozdener ◽  
Carol Dangelmaier ◽  
James L. Daniel ◽  
Satya P. Kunapuli
Keyword(s):  
Protein Kinase C ◽  
Platelet Aggregation ◽  
Protein Kinase ◽  
Response Curve ◽  
Receptor Activation ◽  
Glycoprotein Vi ◽  
Fibrinogen Receptor ◽  
Kinase C ◽  
The Right ◽  
Concentration Response Curve

Abstract Collagen activates platelets by transducing signals through glycoprotein VI (GPVI). It is not clear whether collagen can directly activate fibrinogen receptors on the adherent platelets without a role for positive feedback agonists. We investigated the contribution of secondary G protein signaling to the mechanism of GPVI-stimulated platelet aggregation using the GPVI-selective agonists, convulxin and collagen-related peptide (CRP) as well as collagen. Adenosine diphosphate (ADP) scavengers or ADP receptor antagonists shifted the concentration-response curve slightly to the right at low concentrations of convulxin, whereas platelet aggregation at higher concentrations of convulxin was unaffected by these agents. ADP receptor antagonists shifted the concentration-response curve of collagen- or CRP-induced platelet aggregation to the right at all the concentrations. Protein kinase C inhibitor, Ro 31-8220, or a calcium chelator 5,5′-dimethyl-BAPTA shifted the concentration-response curve of convulxin-induced platelet aggregation to the right. In addition, pretreatment with both Ro 31-8220 and dimethyl-BAPTA resulted in total inhibition of convulxin-mediated aggregation. Blockade of either the calcium- or protein kinase C–regulated pathway leads to inhibition of fibrinogen receptor activation on platelets adherent to collagen, but inhibition of both pathways leads to abolished fibrinogen receptor activation. We conclude that collagen-induced activation of fibrinogen receptor on adherent platelets through GPVI signaling occurs without any significant role for secreted ADP or thromboxane A2. Furthermore, protein kinase C– and calcium-regulated pathways independently contribute to GPVI-mediated platelet aggregation.

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