bluuebunny/crossref_metadata_2025_split huggingface dataset:
CGP 37849 and CGP 39551: novel and potent competitive N‐methyl‐d‐aspartate receptor antagonists with oral activity
Authors: Fagg G.E. , Olpe H.‐R. , Pozza M.F. , Baud J. , Steinmann M. , Schmutz M. , Portet C. , Baumann P. , Thedinga K. , Bittiger H. , Allgeier H. , Heckendorn R. , Angst C. , Brundish D. , Dingwall J.G. 
Published: July 2012

The pharmacological properties of CGP 37849 (dl‐(E)‐2‐amino‐4‐methyl‐5‐phosphono‐3‐pentenoic acid; 4‐methyl‐APPA) and its carboxyethylester, CGP 39551, novel unsaturated analogues of the N‐methyl‐d‐aspartate (NMDA) receptor antagonist, 2‐amino‐5‐phosphonopentanoate (AP5), were evaluated in rodent brain in vitro and in vivo.
Radioligand binding experiments demonstrated that CGP 37849 potently (Ki 220 nm) and competitively inhibited NMDA‐sensitive l‐[3H]‐glutamate binding to postsynaptic density (PSD) fractions from rat brain. It inhibited the binding of the selective NMDA receptor antagonist, [3H]‐(±)‐3‐(2‐carboxypiperazin‐4‐yl)propyl‐1‐phosphonate (CPP), with a Ki of 35 nm, and was 4, 5 and 7 fold more potent than the antagonists ((±)‐cis‐4‐phosphonomethylpiperidine‐2‐carboxylic acid) (CGS 19755), CPP and d‐AP5, respectively. Inhibitory activity was associated exclusively with the trans configuration of the APPA molecule and with the d‐stereoisomer. CGP 39551 showed weaker activity at NMDA receptor recognition sites and both compounds were weak or inactive at 18 other receptor binding sites.
CGP 37849 and CGP 39551 were inactive as inhibitors of l‐[3H]‐glutamate uptake into rat brain synaptosomes and had no effect on the release of endogenous glutamate from rat hippocampal slices evoked by electrical field stimulation.
In the hippocampal slice in vitro, CGP 37849 selectively and reversibly antagonized NMDA‐evoked increases in CA1 pyramidal cell firing rate. In slices bathed in medium containing low Mg2+ levels, concentrations of CGP 37849 up to 10 μm suppressed burst firing evoked in CA1 neurones by stimulation of Schaffer collateral‐commissural fibres without affecting the magnitude of the initial population spike; CGP 39551 exerted the same effect but was weaker. In vivo, oral administration to rats of either CGP 37849 or CGP 39551 selectively blocked firing in hippocampal neurones induced by ionophoretically‐applied NMDA, without affecting the responses to quisqualate or kainate.
CGP 37849 and CGP 39551 suppressed maximal electroshock‐induced seizures in mice with ED50s of 21 and 4 mg kg−1 p.o., respectively.
CGP 37849 and CGP 39551 are potent and competitive NMDA receptor antagonists which show significant central effects following oral administration to animals. As such, they may find value as tools to elucidate the roles of NMDA receptors in brain function, and potentially as therapeutic agents for the treatment of neurological disorders such as epilepsy and ischaemic brain damage in man.
Influence of phorbol esters, and diacylglycerol kinase and lipase inhibitors on noradrenaline release and phosphoinositide hydrolysis in chromaffin cells
Authors: Jones J. Alison , Owen P. Jane , Boarder Michael R. 
Published: July 2012

We have investigated the modification of catecholamine efflux and inositol phosphate formation in cultured adrenal chromaffin cells by tetradecanoyl phorbol acetate (TPA) and inhibitors of diacylglycerol kinase (R 59 022) and diacylglycerol lipase (RG 80267), the two principal pathways of diacylglycerol metabolism.
TPA (1 nm to 1 μm) elicited a slow, calcium‐dependent, sustained release of noradrenaline, which was partially blocked by the dihydropyridine calcium channel blocker (−)‐202 791 and potentiated by the channel enhancer (+)‐202 791.
R 59 022 enhanced noradrenaline efflux at 30 and 50 μm, while the lipase inhibitor RG 80267 failed to elicit release.
Neither R 59 022 nor RG 80267 affected bradykinin‐ or histamine‐stimulated release, but both drugs substantially attenuated nicotine‐ and high K+‐stimulated release.
Pretreatment for 10 min with TPA (but not the relatively inactive 4‐methoxyTPA) or the non‐phorbol protein kinase C stimulator mezerein potently inhibited bradykinin‐ and histamine‐stimulated accumulation of total [3H]‐inositol phosphate; inhibition of [3H]‐inositol phosphate formation was also seen with 24 h TPA treatment.
Neither R 59 022 nor RG 80267, separately or together, affected bradykinin‐stimulated [3H]‐inositol phosphate formation.
Thus while the mechanism exists for inhibition of formation of inositol phosphates by stimulation of protein kinase C, these studies failed to show that this mechanism is activated by agonists acting on phospholipase C linked receptors.
Front‐surface fluorometry with fura‐2 and effects of nitroglycerin on cytosolic calcium concentrations and on tension in the coronary artery of the pig
Authors: Abe Shimako , Kanaide Hideo , Nakamura Motoomi 
Published: July 2012

By use of front‐surface fluorometry and fura‐2‐loaded strips of the coronary artery of the pig, the effects of nitroglycerin (NG) on cytosolic Ca2+ concentrations ([Ca2+]i) and on tension development were measured simultaneously.
Both high K+ depolarization and histamine increased [Ca2+]i and tension in a concentration‐dependent manner. However, the tension development in relation to the [Ca2+]i increase ([Ca2+]i‐tension relation) observed with histamine was much greater than that observed with K+ depolarization.
NG reduced in a concentration‐dependent manner both [Ca2+]i and tension, irrespective of whether the vascular strips were in a resting state or during exposure to high K+ or to histamine stimulation. However, the extent of reduction in tension (relaxation) was greater than that expected from the reduction in [Ca2+]i based on the [Ca2+]i‐tension relationship observed with K+‐depolarization.
In the absence of extracellular Ca2+, NG depleted stored Ca2+ and also inhibited Ca2+ release from histamine‐sensitive stores, but had no effect on the caffeine‐sensitive stores. NG inhibited the caffeine‐induced tension development with no change in [Ca2+]i.
We suggest that NG relaxes the coronary artery of the pig by reducing [Ca2+]i and also by directly controlling contractile elements through second messengers not related to changes in [Ca2+]i.
Effect of intracerebroventricular administration of the GABAB‐receptor agonist baclofen on operant feeding in satiated pigs
Authors: Ebenezer I.S. , Baldwin B.A. 
Published: July 2012

The present study investigated the effects of intracerebroventricular (i.c.v.) administration of the GABAB‐receptor agonist baclofen on food and water intake in satiated pigs previously trained to make operant responses for food and water, which were available ad libitum.
Baclofen (25–100 nmol) i.c.v. produced a dose‐related increase in food intake. Baclofen (50 nmol) increased feeding during the first 15 min after administration (P > 0.01), while the 100 nmol dose increased feeding during the first 30 min (P > 0.01). None of these doses of baclofen had any affect on the daily (24 h) food intake.
The effect of baclofen (50 nmol) on feeding was prevented by pretreating the animals with the GABAB antagonist phaclofen (500 nmol, i.c.v.).
Baclofen (25–100 nmol) i.c.v. had no significant effects on water intake.
Intravenous administration of baclofen (100 nmol) had no effect on food intake, thus eliminating the possibility that i.c.v. baclofen might have stimulated feeding by a peripheral mode of action.
These results show that baclofen increases food intake in satiated pigs, and that this effect is mediated by the drug acting at central GABAB‐receptors.
Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs
Authors: Sassen L.M.A. , Duncker D.J.G.M. , Gho B.C.G. , Diekmann H.W. , Verdouw P.D. 
Published: July 2012

The systemic and regional haemodynamic effects of the potassium channel activator EMD 52692 or its solvent were investigated after intravenous and after intracoronary administration in anaesthetized pigs.
Consecutive intravenous 10 min infusions of EMD 52692 (0.15, 0.30, 0.60, 1.20 μg kg−1 min−1; n = 7) dose‐dependently decreased mean arterial blood pressure by up to 50%. This was entirely due to peripheral vasodilatation, since cardiac output did not change. Heart rate increased by up to 50%, while left ventricular end diastolic pressure decreased dose‐dependently from 6 ± 1 mmHg to 3 ± 1 mmHg (P > 0.05), and stroke volume decreased from 30 ± 2 ml to 21 ± 2 ml (P > 0.05). Left ventricular dP/dtmax was not affected.
Although cardiac output did not change, EMD 52692 caused a redistribution of blood flow from the arteriovenous anastomoses to the capillary channels. Blood flow to the adrenals, small intestine, stomach, bladder, spleen and brain increased, while renal blood flow decreased and blood flow to several muscle groups and skin were not altered. Vascular conductance was increased dose‐dependently in all organs, except for the kidneys, where after the initial increase, vascular conductance returned to baseline with the highest dose. Particularly striking were the effects on the vasculature of the brain. With the highest dose of EMD 52692 blood flow more than doubled, while vascular conductance increased four fold.
Transmural myocardial blood flow increased slightly, which was entirely due to an increase in subepicardial blood flow. Myocardial O2‐consumption and segment length shortening were not significantly affected.
After consecutive 10 min intracoronary infusions (0.0095, 0.019, 0.0375 and 0.075 μg kg−1 min−1; n = 7) into the left anterior descending coronary artery (LADCA), mean arterial blood pressure was maintained with the lowest two doses, but decreased by up to 15% with the higher doses, whereas heart rate increased by up to 24%. Blood flow to the LADCA‐perfused myocardium doubled with the highest dose, the subepicardium benefitting the most. Coronary venous O2‐saturation increased dose‐dependently from 23 ± 2% to 60 ± 4%, while myocardial O2‐consumption of the LADCA‐perfused myocardium was not affected by the drug.
It is concluded that EMD 52692 is a potent vasodilator, with particularly pronounced effects on vasculature of the brain. Its selectivity for vascular smooth muscle cells exceeds that for the myocytes, since with doses that are much higher than those of potential clinical interest no negative inotropic effects were observed. The compound primarily dilates arteries but some venodilatation may also occur.
Behavioural evidence for functional interactions between 5‐HT‐receptor subtypes in rats and mice
Authors: Berendsen Hemmie H.G. , Broekkamp Chris L.E. 
Published: July 2012

Different 5‐hydroxytryptamine (5‐HT) receptor subtypes mediate different behavioural responses. Compounds acting at more than one 5‐HT receptor exert behavioural effects which may be the result of response competition or a specific interaction between pathways within the CNS. Therefore the mutual interaction between different 5‐HT receptor subtypes was studied.
Hypothermia and hypoactivity in mice induced by the 5‐HT1A‐agonist 8‐hydroxy‐dipropylaminotetralin (8‐OH‐DPAT) could be attenuated by the preferential 5‐HT1C‐agonists MK 212, 1‐(meta‐chlorophenyl)‐piperazine (mCPP) and m‐trifluoromethyl phenyl piperazine (TFMPP), and by the mixed 5‐HT2/1C‐agonist 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI). The mixed 5‐HT1A/1B‐agonist CGS 12066B at 10 mg kg−1 potentiated hypothermia and had no effect on hypoactivity.
Forepaw treading in rats induced by the 5‐HT1A‐agonist 8‐OH‐DPAT was attenuated by the 5‐HT1C‐agonists MK 212 and mCPP. The 5‐HT1C‐agonist TFMPP had a bimodal effect: at low doses (> 1 mg kg−1) it potentiated, and at higher doses (> 2.2 mg kg−1) it attenuated forepaw treading. the mixed 5‐HT2/1C‐agonist DOI produced 5‐HT2‐related behaviours and potentiated 8‐OH‐DPAT‐induced forepaw treading. This indicates an attenuating effect of 5‐HT1C‐receptor activation and a potentiating effect of 5‐HT2‐receptor activation. CGS 12066B had no effect in this respect.
Head shakes in rats induced by DOI could be attenuated by 8‐OH‐DPAT, TFMPP, mCPP and MK 212. The ID50s were 0.03, 0.7, 0.1 and 2 mg kg−1, respectively. This suggests that a 5‐HT2‐receptor‐mediated effect may be attenuated by activation of 5‐HT1A‐ or 5‐HT1C‐receptors. CGS 12066B attenuated the head shake response but only at 10 mg kg−1.
The results suggest that interactions exist between the different 5‐HT receptor subtype‐mediated events. Therefore, care is needed in drawing conclusions from functional measurements when compounds have more or less equal affinities for more than one 5‐HT‐receptor subtype.
The effects of cocaine on intracellular Ca2+ handling and myofilament Ca2+ responsiveness of ferret ventricular myocardium
Authors: Perreault Cynthia L. , Hague Nancy L. , Ransil Bernard J. , Morgan James P. 
Published: July 2012

When ferret right ventricular papillary muscles were stimulated with threshold punctate pulses (0.33 Hz; 30°C), cocaine, 10−5 m, increased peak tension development from 815 ± 120 to 1125 ± 180 mg (P > 0.05) and increased the rate of relaxation from peak tension (time to 80% decline from peak tension decreased from 155 ± 11 to 144 ± 11 ms; P > 0.05). These changes in the twitch were associated with comparable changes in the amplitude and time course of the calcium transient measured with aequorin (amplitude increased from 62 ± 4 to 90 ± 7% (P > 0.05) of maximal values; time to 80% decline from peak amplitude decreased from 84 ± 8 to 64 ± 3 ms; P > 0.05). These effects were markedly attenuated in the presence of the β‐adrenoceptor‐blocking agent, propranolol, 6 × 10−7 m, or by maximization of catecholamine release from the adrenergic nerve endings with field pulses of supratheshold strength, indicating that catecholamine release from the adrenergic nerve endings is responsible for the positive inotropic and lusitropic responses to low and moderate doses of cocaine (i.e., ≤ 10−5 m).
High doses of cocaine (i.e., > 10−5 m) produced negative inotropic and lusitropic effects that were associated with a decreased amplitude and prolonged duration of the calcium transient.
In aequorin‐loaded intact fibres, cocaine 10−5 m did not affect the force‐calcium relationship unless catecholamines were present. Cocaine, 10−5 m, significantly shifted the force‐calcium relationship of saponin‐skinned muscles (pCa50 = 6.14 ± 0.05 versus 5.92 ± 0.07; P > 0.05), indicating reduced responsiveness of the myofilaments to calcium. Fmax (maximal Ca2+‐activated force) was reduced to 58% of control in the presence of 10−5 m cocaine, while the slope of the calcium‐force curve remained unchanged. These data indicate that cocaine may also decrease myofilament calcium sensitivity and maximal calcium‐activated force, via mechanisms independent of catecholamines, when cellular diffusion barriers are eliminated.
Nitrendipine decreases benzodiazepine withdrawal seizures but not the development of benzodiazepine tolerance or withdrawal signs
Authors: Dolin S.J. , Patch T.L. , Rabbani M. , Siarey R.J. , Bowhay A.R. , Little H.J. 
Published: July 2012

The effects of the calcium channel blocking agent, nitrendipine, were studied on seizures in mice produced during withdrawal from chronic benzodiazepine treatment and on the development of tolerance to benzodiazepines.
Nitrendipine produced a dose‐dependent decrease in seizure incidence, when seizures were produced by the partial inverse agonist FG7142 during withdrawal from seven days treatment with flurazepam.
Nitrendipine did not raise the seizure thresholds in naïve mice to the full inverse agonist methyl‐6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM), or to the γ‐aminobutyric acid (GABA) antagonist, bicuculline.
When given concurrently with flurazepam for seven days, nitrendipine did not affect the incidence of seizures during flurazepam withdrawal.
When given concurrently with the benzodiazepines, nitrendipine did not prevent the development of tolerance to midazolam general anaesthesia or tolerance to the ataxic actions of flurazepam or midazolam.
Chronic treatment with flurazepam for seven days did not affect the Kd or Bmax of [3H]‐nimodipine binding in mouse whole brain or cerebral cortex.
These results with benzodiazepines are partially in contrast with those for ethanol, where nitrendipine not only decreased ethanol withdrawal seizures when given acutely, but also prevented the development of tolerance and withdrawal signs when given concurrently with ethanol. However, they do confrm the selectivity of nitrendipine for withdrawal‐induced seizures.
Inhibitory effect of 5‐hydroxytryptamine on penile erectile function in the rat
Authors: Finberg J.P.M. , Vardi Y. 
Published: July 2012

An increase in corporal pressure was elicited in pithed rats by stimulation of the sacral part of the spinal cord. This response was inhibited by intravenous injection of 5‐hydroxytryptamine (5‐HT) (ED50 = 28.5 ± 2.2 μg kg−1).
The inhibitory effect of 5‐HT was blocked by methysergide and methiothepin (each 1 mg kg−1), but not by ketanserin (0.02 mg kg−1), MDL 72222 (1 mg kg−1) or prazosin (0.1 mg kg−1).
An inhibitory effect on the corporal pressure response to spinal stimulation was also produced by 5‐carboxyamidotryptamine (ED50 = 5.6 ± 2.8 μg kg−1), but not by m‐chlorophenylpiperazine (mCPP), RU 24969, 8‐hydroxy‐2‐[di‐n‐propyl‐amino]‐tetralin (8‐OH‐DPAT) or fenfluramine (doses up to 1–2 mg kg−1).
Neither methiothepin (1 mg kg−1) nor clomipramine (1 mg kg−1) had any effect on the frequency‐response curve for increase in corporal pressure by spinal stimulation.
The results indicate that 5‐HT exerts an inhibitory action on penile erection by a peripheral mechanism. This effect may be mediated by vasoconstriction in cavernosal vessels, or inhibition of release of a vasodilator neurotransmitter. From the spectrum of agonist and antagonist responses, the receptor involved may be of the 5‐HT1D subtype.
Characterization of responses to cromakalim and pinacidil in smooth and cardiac muscle by use of selective antagonists
Authors: McPherson Grant A. , Angus James A. 
Published: July 2012

In dog isolated coronary artery (precontracted with endothelin, 10 nm) cromakalim (0.1–30μm) and pinacidil (1–30μm) produced concentration‐dependent vasorelaxant responses. The effects of these compounds could be blocked by glibenclamide (3μm), phentolamine (30 μm) or alinidine (30 μm) to a similar extent, indicating that both agents alter vascular tone through the same mechanism in this preparation.
The ability of the antagonists glibenclamide, phentolamine and alinidine to block the response to cromakalim in a number of smooth muscle types from the guinea‐pig was determined. Cromakalim (0.1–30 μm) produced concentration‐dependent relaxant responses in thoracic aorta (precontracted with endothelin, 30 nm), ileum (precontracted with K+, 25 mm) and trachea (spontaneously contracted). Responses to cromakalim in all tissues could be blocked by the three antagonists. However, significantly higher concentrations of the antagonists were required to block responses in the thoracic aorta than in the ileum or trachea. Given that the rank order of potency of the antagonists was similar in all tissues (i.e. glibenclamide > phentolamine = alinidine), this result may suggest vascular K+ channels opened by cromakalim are quantitatively but not qualitatively different in vascular compared with non‐vascular smooth muscle. Glibenclamide was approxmately 10 times more potent than phentolamine or alinidine.
Cromakalim had minimal functional effects on the rat spontaneously beating right atrial (rate) or electrically driven left ventricular strip (force) preparations. Similarly the three antagonists studied failed to alter force generation in the right ventricular strip. However alinidine and phentolamine did produce a dose‐related bradycardia in the spontaneously beating right atria. This effect appears to be unrelated to blockade of the K+ channel opened by cromakalim since glibenclamide, the most potent K+ channel antagonist studied, failed to produce the same response.
It would appear that the K+ channel opened by cromakalim is present in a number of vascular and non‐vascular smooth muscle. Based on the potency of the three antagonists studied, there appears to be little heterogeneity in the process activated by cromakalim in vascular and non‐vascular smooth muscle.
Renal vascular responsiveness to arachidonic acid in experimental diabetes
Authors: Quilley J. , McGiff J.C. 
Published: July 2012

Isolated perfused kidneys from diabetic rats (duration 4–6 and 20–24 weeks) were more sensitive to the vasoconstrictor effects of arachidonic acid than kidneys from age‐matched control rats. Sensitivity diminised with age in both control and diabetic groups.
The enhanced vasoconstrictor effect of arachidonic acid in diabetic rat kidneys was associated with increased conversion to prostaglandins.
The renal vasoconstrictor response to arachidonic acid in both groups was reduced by thromboxane A2/prostaglandin H2 receptor antagonism but not by inhibition of thromboxane synthase.
Diabetic rat kidneys were also more sensitive to the vasoconstrictor effects of the endoperoxide analogue, U46619, while vasoconstrictor responses to phenylephrine were not markedly different from those of control rat kidneys.
In conclusion, prostaglandin endoperoxides appear to mediate arachidonic acid‐induced vasoconstriction in diabetic and control rat kidneys. The enhanced renal vasoconstrictor response to arachidonic acid in diabetic rats results from increased sensitivity to endoperoxides and increased formation of endoperoxides from arachidonic acid.
A calcium channel antagonist stereoselectively decreases ethanol withdrawal hyperexcitability but not that due to bicuculline, in hippocampal slices
Authors: Whittington M.A. , Little H.J. 
Published: July 2012

Extracellular recordings were made from CA1 area of isolated hippocampal slices of the mouse after chronic ethanol administration in vivo, with orthodromic stimulation of the Schaffer collateral/commissural fibres.
The (+)‐isomer of the calcium channel antagonist PN 200–110 (isradipine) significantly decreased all the recorded signs of hyperexcitability in the slices during ethanol withdrawal. These included increased paired pulse potentiation and decreases in the thresholds for elicitation of single and multiple population spikes.
The (–)‐isomer of PN 200–100 did not affect ethanol withdrawal hyperexcitability in the slices.
Neither isomer of PN 200–110 affected the field potentials in slices from control animals.
The γ‐aminobutyric acid (GABA) antagonist, bicuculline, lowered thresholds for eliciting population spikes in hippocampal slices from untreated animals. The active, (+)‐isomer of PN 200–110 did not affect this action of bicuculline in hippocampal slices from untreated animals.
The stereoisomerism of the action of PN 200–110 on ethanol withdrawal hyperexcitability in the hippocampal slice was therefore the same as that seen in blockade of calcium channels. The results suggested that ethanol withdrawal hyperexcitability recorded in the isolated hippocampal slice involved increased activity of voltage‐sensitive calcium channels.