Antagonist properties of arylaminopyridazine GABA derivatives at the Ascaris muscle GABA receptor

1991 ◽  
Vol 159 (1) ◽  
pp. 149-164
Author(s):  
A. H. Duittoz ◽  
R. J. Martin
Keyword(s):  
Gabaa Receptor ◽  
Binding Sites ◽  
Gaba Receptor ◽  
Dissociation Constants ◽  
Ascaris Suum ◽  
Antagonistic Activity ◽  
Maximal Response ◽  
Response Curves ◽  
Gaba Derivatives ◽  
The Right

1. In a previous study, it was shown that the potency order for two arylamino-pyridazine derivatives, SR95531 and SR95103, was different in Ascaris suum when compared to vertebrate preparations. SR95531, the most potent analogue at the vertebrate GABAA receptor, was found to be very weak at antagonizing GABA responses in Ascaris, but SR95103, approximately 20 times less potent than SR95531 in vertebrate preparations, was more potent than SR95531 in Ascaris. These results suggested the existence of different accessory binding sites at the Ascaris GABA receptor. 2. To test this hypothesis, the effects of a series of arylaminopyridazine derivatives of GABA on the GABA response in Ascaris suum muscle were investigated using a two-microelectrode current-clamp technique. 3. The results showed that SR42627, a potent antagonist at the GABAA receptor, was one of the weakest analogues in Ascaris muscle. In contrast, SR95132, virtually inactive in vertebrate preparations, was equipotent to SR95103, the most potent analogue of the series in Ascaris muscle. 4. The three most potent analogues in Ascaris, SR95103, SR95132 and SR42666, displace GABA dose-response curves to the right without decreasing the maximal response. The modified Schild plots for these compounds are consistent with a competitive mechanism involving two molecules of GABA and only one molecule of antagonist interacting with the receptor. The estimated dissociation constants for SR95103, SR95132 and SR42666 are, respectively, 64, 65 and 105 mumol l-1. 5. Structure-activity relationships for this series of compounds were examined in Ascaris and compared to those in vertebrates. Substitution on the pyridazine ring in the 4-position, while detrimental for the antagonist potency at the vertebrate GABAA receptor, appears to be a prerequisite for antagonistic activity on the Ascaris muscle GABA receptor. These results are interpreted in terms of the accessory binding site theory of Ariens, and suggest the existence of different accessory binding sites on the Ascaris GABA receptor.

scholarly journals Early Effects of Tetraethylammonium Chloride on the Contractile Properties of Isolated Rabbit Basilar Arteries

1987 ◽  
Vol 7 (2) ◽  
pp. 237-247 ◽  
Author(s):  
A. R. Young ◽  
H. Säveland ◽  
J. D. Pickard ◽  
S. Perry ◽  
L. Brandt ◽  
...  
Keyword(s):  
Potassium Conductance ◽  
Cerebrovascular Reactivity ◽  
Maximal Response ◽  
Induced Response ◽  
Response Curves ◽  
Vascular Effects ◽  
Extracellular Medium ◽  
Tetraethylammonium Chloride ◽  
Basilar Arteries ◽  
The Right

The acute vascular effects of tetraethylammonium chloride (TEA) were examined on annular segments of rabbit basilar arteries, Contractions induced by the potassium channel blocker were compared with those obtained for potassium chloride, 5-hydroxytryptamine (5-HT) and norepinephrine (NE), The greater magnitude of the contractions was of the following order: [K+] > 5-HT> TEA> NK High concentrations of TEA alone (10−2 M) generated spontaneous oscillatory contractions in cerebral vessels that were normally quiescent, Low concentrations of TEA (10−8-10−6 M), which had no vasomotor properties per se, enhanced the contractile response of submaximal concentrations of 5-HT (10−7 M) and NE (3 × 10−6 M) and attenuated the contraction produced by 60 m M [K+], An increased vascular response to the amines was still evident up to 3 h after the addition of TEA despite frequent rinsing with fresh buffer solutions. On arteries precontracted with TEA (10−2 M), but not high [K +], the subsequent addition of 5-HT (10−7 M) still induced a powerful constriction. Repeated concentration-response curves for [K+] were reproducible and, in the presence of TEA (10−8 or 10−6 M), the curve was displaced to the right in a competitive manner. A higher concentration of TEA (10−4 M) was devoid of any blocking properties on the [K+]-induced response whereas, at 10−3 M TEA, the response was potentiated, as evidenced by a shift of the curve to the left. Interactions between TEA and the cumulative response to 5-HT were difficult to interpret. Repeated exposures of the artery to 5-HT resulted in an increased maximal response with each determination (EAm = 127 ± 9% and 149 ±: 14% of control values following the second and third applications, respectively). With TEA (10−6 M), the increase in the maximal contractile effect noted previously was not observed. Contractions induced by single concentrations of TEA (10−2 M) or [K+] (60 m M) were calcium dependent, were abolished completely in a calcium-free medium, and were depressed by the calcium antagonist nimodipine. 5-Hydroxytryptamine-induced contractions (10−5 M) were less sensitive to withdrawal of calcium from the extracellular medium (31 ± 6% relative to the maximal response at 4 m M calcium). Hence, an acute reduction in potassium conductance in cerebrovascular smooth muscle produced by TEA has complex, concentration-dependent effects and reproduces only part of the spectrum of effects of cisternal injection of blood on cerebrovascular reactivity.

II. Pharmacology of Angiotensin Antagonists

1973 ◽  
Vol 51 (2) ◽  
pp. 114-121 ◽  
Author(s):  
D. Regoli ◽  
W. K. Park ◽  
F. Rioux
Keyword(s):  
Slow Rate ◽  
Response Curve ◽  
Receptor Site ◽  
Maximal Response ◽  
Pharmacological Properties ◽  
Response Curves ◽  
Onset Of Action ◽  
Competitive Antagonist ◽  
Long Acting ◽  
The Right

The pharmacological properties of three antagonists of angiotensin II (ATII) have been characterized on the rat isolated stomach strip.(8-Gly)-ATII, a newly synthesized antagonist of ATII, as well as (8-Leu)-ATII and (1-Sar-8-Leu)-ATII displace to the right the dose–response curve of ATII and the displacement is proportional to the dose of antagonist.Dose–response curves of ATII remain parallel to that of the control in the presence of (8-Gly)-ATII and (8-Leu)-ATII, while parallelism is lost with (1-Sar-8-Leu)-ATII. This antagonist also depresses the maximal response to ATII.All data presented in this paper indicate that (8-Gly)-ATII and (8-Leu)-ATII are competitive antagonists of ATII with different affinities for the receptors, (8-Gly)-ATII being about 12 times less potent than (8-Leu)-ATII. This compound competes with ATII on a one to one basis: pA2 of (8-Leu)-ATII has the same value as pD2 of ATII.(1-Sar-8-Leu)-ATII does not fulfil the criteria of a competitive antagonist. This compound is very potent and the onset of action is as rapid (5 min) as for the other two compounds. All data obtained with (1-Sar-8-Leu)-ATII are consistent with the assumption that this compound is competitive in the sense that it acts on the same receptor site as ATII, but owing probably to slow rate of inactivation by tissue aminopeptidases, it dissociates slowly from the receptors and it acts as a specific long-acting antagonist.

Analysis of receptor reserves in canine tracheal smooth muscle

1987 ◽  
Vol 62 (4) ◽  
pp. 1755-1758 ◽  
Author(s):  
S. J. Gunst ◽  
J. Q. Stropp ◽  
N. A. Flavahan
Keyword(s):  
Smooth Muscle ◽  
Connective Tissue ◽  
Dissociation Constants ◽  
Receptor Occupancy ◽  
Ringer Solution ◽  
Isometric Tension ◽  
Maximal Response ◽  
Response Curves ◽  
Receptor Reserve ◽  
Partial Inactivation

The receptor reserves for acetylcholine, 5-hydroxytryptamine, and histamine in canine tracheal muscle were evaluated. Muscle strips were dissected free of epithelial and connective tissue and suspended for isometric tension recording in modified Krebs-Ringer solution. Dissociation constants for all three agonists were determined by analysis of their concentration-response curves under control conditions and after partial inactivation of receptors by phenoxybenzamine dihydrochloride. The values of KA for acetylcholine, 5-hydroxytryptamine, and histamine were 1.8 X 10(-5) M, 1.35 X 10(-6) M, and 5.0 X 10(-5) M, respectively. Dissociation constants were used to determine receptor occupancy-response relationships. Maximal responses to acetylcholine were obtained by activation of only 4.0 +/- 1.0% of receptors, indicating the presence of a very large receptor-reserve. In contrast, a maximal response to 5-hydroxytryptamine and histamine required activation of 78.0 +/- 11.0 and 87.7 +/- 1.6% of the receptors, respectively, indicating very modest receptor reserves. The differences in receptor-reserve characteristics for these agonists in airway muscle might contribute to the differential effects of inhibitory and facilitory influences on contractions elicited by them.

Fat metabolism in human obesity

1994 ◽  
Vol 266 (4) ◽  
pp. E600-E605 ◽  
Author(s):  
P. J. Campbell ◽  
M. G. Carlson ◽  
N. Nurjhan
Keyword(s):  
Insulin Resistance ◽  
Fat Mass ◽  
Dose Response ◽  
Insulin Dose ◽  
Fat Free Mass ◽  
Maximal Response ◽  
Response Curves ◽  
Ffa Metabolism ◽  
Obese Subjects ◽  
The Right

Excessive fat turnover and oxidation might cause the insulin resistance of carbohydrate metabolism in obese humans. We studied the response of free fatty acid (FFA) metabolism in lean and obese volunteers to sequential insulin infusions of 4, 8, 25, and 400 mU.m-2.min-1. The insulin dose-response curves for suppression of FFA concentration, FFA turnover ([1-14C]palmitate), and lipolysis ([2H5]glycerol) were shifted to the right in the obese subjects (insulin concentrations that produced a half-maximal response, lean vs. obese: 103 +/- 21 vs. 273 +/- 41, 96 +/- 11 vs. 264 +/- 44, and 101 +/- 23 vs. 266 +/- 44 pM, all P < 0.05), consistent with insulin resistance of FFA metabolism in obesity. After the overnight fast, FFA turnover per fat mass was decreased in obese subjects (37 +/- 4 vs. 20 +/- 3 mumol.kg fat mass-1.min-1, P < 0.01) as the result of suppression of lipolysis by the hyperinsulinemia of obesity and an increased fractional reesterification of FFA before leaving the adipocyte (primary FFA reesterification; 0.14 +/- 0.03 vs. 0.35 +/- 0.06, P < 0.05). Nevertheless, FFA turnover per fat-free mass (FFM) was also greater in the obese volunteers (8.5 +/- 0.7 vs. 11.0 +/- 1.0 mumol.kg FFM-1.min-1, P < 0.05) but only as the result of increased reesterification of intravascular FFA (secondary reesterification; 1.8 +/- 0.5 vs. 4.8 +/- 1.1 mumol.kg FFM-1.min-1, P < 0.01), since FFA oxidation was the same in the two groups throughout the insulin dose-response curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Dissociation constants (KA) and relative efficacies of sympathomimetic amines in isolated atria during hypothermia-induced supersensitivity

1983 ◽  
Vol 61 (6) ◽  
pp. 572-580 ◽  
Author(s):  
Kenneth J. Broadley ◽  
John H. McNeill
Keyword(s):  
Dose Response ◽  
Dissociation Constants ◽  
Response Curves ◽  
Isolated Atria ◽  
Adrenoceptor Agonists ◽  
Dose Response Curves ◽  
The Right ◽  
Tension Curves ◽  
Noradrenaline And Adrenaline ◽  
Right Atria

Hypothermia increases the sensitivity of isolated cardiac muscle to stimulation by β-adrenoceptor agonists. The purpose of this study was to determine pharmacologically whether this supersensitivity is associated with a change in the affinity of agonists for the receptor. The positive inotropic and chronotropic responses of guinea-pig paced left and spontaneously beating right atria were recorded. Cumulative dose–response curves to noradrenaline (or adrenaline) were compared with isoproterenol in each tissue. At 38 °C, the rate curves were to the left of the tension curves, with lower mean effective concentration (EC50) values. However, this difference was less for noradrenaline and adrenaline which were therefore tension selective relative to isoproterenol. Lowering the temperature to 25 °C induced supersensitivity, all dose–response curves being displaced to the left. In the presence of carbachol the curves were shifted to the right with depression of the maxima. Dissociation constants (KA) were calculated from plots of reciprocals of equiactive concentrations obtained before and in the presence of carbachol. KA values for rate and tension responses of each agonist were identical at 38 °C, indicating that the rate selectivity was not due to affinity differences. The efficacies (er) of noradrenaline and adrenaline were greater than isoproterenol for tension, but smaller for rate responses, which may explain their relative tension selectivity. At 25 °C the KA values of all agonists were reduced approximately 10-fold. Hypothermia-induced supersensitivity is therefore associated with an increase in affinity for the cardiac β-adrenoceptor.

Effects of Lidocaine and Procaine on Canine Nasal Blood Vessels

1988 ◽  
Vol 97 (4) ◽  
pp. 409-413 ◽  
Author(s):  
Hsing-Won Wang ◽  
Richard T. Jackson
Keyword(s):  
Blood Vessels ◽  
Nasal Mucosa ◽  
Dose Response ◽  
Response Curve ◽  
Smooth Muscle Contraction ◽  
Dose Response Curve ◽  
Maximal Response ◽  
Field Stimulation ◽  
Response Curves ◽  
The Right

The effects of lidocaine and procaine on contractile responses of isolated canine nasal mucosal blood vessels to field stimulation and methoxamine were investigated. Analysis of cumulative dose-response curves showed that the two local anesthetics antagonized methoxamine and inhibited the field-stimulation response. The latter effect was interpreted as due to the blockade of Na+channels. This would inhibit nerve conduction induced by field stimulation. The former effect on methoxamine is probably caused by the effect of these anesthetics on the mobilization of Ca++ needed for smooth muscle contraction. Preincubation of the nasal mucosa with low doses of procaine or lidocaine shifts the methoxamine dose-response curve to the right. With higher doses, the maximal response is also reduced. The shift of the dose-response curve showed that procaine or lidocaine can change the α-adrenergic receptor affinity. Commercial 1% lidocaine with 1:100,000 epinephrine also inhibits field stimulation and antagonizes methoxamine contractions. Lidocaine can increase the basal tone of nasal mucosa, while procaine cannot. From these results, we conclude that procaine and lidocaine have common mechanisms in blocking Na+ channels but differ in their ability to modify Ca++ stores or channels.

Human syncytiotrophoblast NPY receptors are located on BBM and activate PLC-to-PKC axis

1998 ◽  
Vol 274 (3) ◽  
pp. E502-E509 ◽  
Author(s):  
Jacques Robidoux ◽  
Lucie Simoneau ◽  
Serge St-Pierre ◽  
Hafid Ech-Chadli ◽  
Julie Lafond
Keyword(s):  
Binding Sites ◽  
Plasma Membranes ◽  
Peptide Yy ◽  
Binding Capacity ◽  
Rank Order ◽  
Receptor Activation ◽  
Response Curves ◽  
Pi3k Activation ◽  
Basal Plasma ◽  
The Right

Neuropeptide Y (NPY) is abundant in plasma and amniotic fluid of women throughout pregnancy, during which its involvement in placental hormonogenesis has been proposed. In accordance with its putative role, the aim of this study was to characterize the human placental syncytiotrophoblast receptivity to NPY. Thus we performed this study on brush-border membranes (BBM) and basal plasma membranes (BPM). Specific125I-labeled NPY (125I-NPY) binding to BBM was rapid (20 min), saturable, with a maximum binding capacity of 604 ± 100 fmol/mg protein, and of high affinity, with a dissociation constant of 11 ± 3 nM. No saturable binding could be shown in BPM. The rank order of affinity of NPY and related peptides to compete for 125I-NPY binding sites was peptide YY (PYY) > NPY = [Leu31,Pro34]NPY > 13–36NPY >> pancreatic polypeptide (PP). It is noteworthy that PYY displaced only 45% of the binding sites. In BBM, both NPY and PYY were potent phospholipase C (PLC) stimulators, leading to a four- to fivefold increase of control phosphodiesterase activity. The latter effect could be prevented by preincubation of membranes with 5 μM U-73122, a known inhibitor of G protein-linked receptor activation of PLC-β. Furthermore, 5 μM BIBP-3226, a Y1-receptor antagonist, shifted both dose-response curves to the right in a similar fashion for both peptides. In accordance with the PLC stimulation, both peptides also induced stimulation of protein kinase C (PKC) activity, which could be partially but additively prevented by U-73122 and LY-294002, a selective inhibitor of phosphatidylinositol-3 kinase (PI3K). Taken together, these data suggest that placental and blood-derived NPY binds to a mixed population of receptors composed of Y1 and Y3 subtypes on the maternal side of the syncytiotrophoblast, where it can mediate its physiological purposes via PLC-β and PI3K activation, both of which lead to PKC activation. However, because BIBP-3226 antagonized both effects, the physiological relevance of the apparent Y3 fraction is still unsolved.

scholarly journals Rates and equilibria for a photoisomerizable antagonist at the acetylcholine receptor of Electrophorus electroplaques.

1985 ◽  
Vol 86 (2) ◽  
pp. 235-256 ◽  
Author(s):  
M E Krouse ◽  
H A Lester ◽  
N H Wassermann ◽  
B F Erlanger
Keyword(s):  
Dissociation Constants ◽  
Light Flash ◽  
Dissociation Rate ◽  
Dose Ratio ◽  
Response Curves ◽  
Competitive Antagonism ◽  
Cis And Trans Isomers ◽  
Order Of Magnitude ◽  
Dissociation Rate Constants ◽  
The Right

Voltage-jump and light-flash experiments have been performed on isolated Electrophorus electroplaques exposed simultaneously to nicotinic agonists and to the photoisomerizable compound 2,2'-bis-[alpha-(trimethylammonium)methyl]-azobenzene (2BQ). Dose-response curves are shifted to the right in a nearly parallel fashion by 2BQ, which suggests competitive antagonism; dose-ratio analyses show apparent dissociation constants of 0.3 and 1 microM for the cis and trans isomers, respectively. Flash-induced trans----cis concentration jumps produce the expected decrease in agonist-induced conductance; the time constant is several tens of milliseconds. From the concentration dependence of these rates, we conclude that the association and dissociation rate constants for the cis-2BQ-receptor binding are approximately 10(8) M-1 s-1 and 60 s-1 at 20 degrees C; the Q10 is 3. Flash-induced cis----trans photoisomerizations produce molecular rearrangements of the ligand-receptor complex, but the resulting relaxations probably reflect the kinetics of buffered diffusion rather than of the interaction between trans-2BQ and the receptor. Antagonists seem to bind about an order of magnitude more slowly than agonists at nicotinic receptors.

Competitive antagonism of pressor responses to angiotensin II and angiotensin III by the angiotensin II-1 receptor ligand losartan

1992 ◽  
Vol 70 (5) ◽  
pp. 716-719 ◽  
Author(s):  
Aly Abdelrahman ◽  
Catherine C. Y. Pang
Keyword(s):  
Angiotensin Ii ◽  
Dose Response ◽  
Dissociation Constants ◽  
Ang Ii ◽  
Receptor Ligands ◽  
Response Curves ◽  
Competitive Antagonism ◽  
Angiotensin Iii ◽  
Dose Response Curves ◽  
The Right

Losartan (DuP 753) and PD123177 are nonpeptide angiotensin (ANG) receptor ligands for subtypes of ANG II receptors ANG II-1 and ANG II-2, respectively. We examined the effects of losartan and PD123177 on dose – mean arterial pressure (MAP) response curves for ANG II and ANG III in eight groups (n = 6 each) of conscious rats. Saline (0.9% NaCl), losartan (1 × 10−6 and 9 × 10−6 mol/kg), and PD123177 (2 × 10−5 mol/kg) were i.v. bolus injected 15 min before the construction of ANG II dose–response curves in groups I, II, III, and IV, respectively. Groups V–VIII were treated similarly to I–IV except that ANG III was given in place of ANG II. Losartan dose dependently shifted the dose–response curves of ANG II and ANG III to the right with similar dissociation constants (−log KI of 6.6 ± 0.7 and 6.6 ± 0.1 mol/kg, respectively) and no change in the maxima. PD123177 affected neither maximum MAP nor ED50 values for ANG II or ANG III. Our results show that losartan but not PD123177 is a competitive antagonist of the MAP effects of ANG II and ANG III.Key words: nonpeptide angiotensin receptor antagonist, angiotensin II, angiotensin III, blood pressure, losartan.

scholarly journals Local anesthetics QX 572 and benzocaine act at separate sites on the batrachotoxin-activated sodium channel.

1981 ◽  
Vol 77 (2) ◽  
pp. 137-153 ◽  
Author(s):  
L M Huang ◽  
G Ehrenstein
Keyword(s):  
Sodium Channels ◽  
Dose Response ◽  
Binding Sites ◽  
Local Anesthetics ◽  
Dissociation Constants ◽  
Response Curves ◽  
Single Class ◽  
Site Model ◽  
Mouse Neuroblastoma ◽  
Competitive Inhibitors

We have studied the effect of local anesthetics QX 572, which is permanently charged, and benzocaine, which is neutral, on batrachotoxin-activated sodium channels in mouse neuroblastoma N18 cells. The dose-response curves for each drug suggest that QX 752 and benzocaine each act on a single class of binding sites. The dissociation constants are 3.15 X 10(-5) M for QX 572 and 2.65 X 10(-4) M for benzocaine. Equilibrium and kinetic experiments indicate that both drugs are competitive inhibitors of batrachotoxin. When benzocaine and QX 572 are present with batrachotoxin, they are much more effective at inhibiting Na+ flux than would be predicted by a one-site model. Our results indicate that QX 572 and benzocaine bind to separate sites, each of which interacts competitively with batrachotoxin.

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