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PubMed2004

Overexpression of beta 1-adrenoceptors in adult rat ventricular myocytes enhances CGP 12177A cardiostimulation: implications for 'putative' beta 4-adrenoceptor pharmacology.

1. CGP 12177A mediates cardiostimulation by activation of the 'putative' beta(4)-adrenoceptor; however, it has recently been reported that disruption of the beta(1)-adrenoceptor gene abolishes this effect. We have adenovirally overexpressed beta(1)-adrenoceptors in isolated, cultured adult rat ventricular cardiomyocytes and observed the inotropic potency of isoprenaline and CGP 12177A (in the presence of 1 microm propranolol). 2. Isoprenaline was a full inotropic agonist at rat ventricular myocytes (pD(2) 7.69+/-0.12). CGP 12177A was a nonconventional partial agonist (pD(2) 6.34+/-0.09), increasing inotropy and lusitropy, with an intrinsic activity of 0.34 and antagonised by bupranolol. 3. beta(1)-adrenoceptor overexpression enhanced the inotropic potency of isoprenaline by 11.7-fold (pD(2) 8.76+/-0.14) and CGP 12177A by 5.9-fold (7.11+/-0.10), respectively. Green fluorescent protein (GFP) overexpression did not alter the potency of isoprenaline or CGP 12177A (pD(2) 7.41+/-0.24 and pD(2) 6.60+/-0.50, respectively). 4. The cardiostimulant effects of CGP 12177A were enhanced by IBMX (phosphodiesterase inhibitor) and decreased by Rp-cAMPS (cAMP antagonist). CGP 12177A also increased cAMP levels. CGP 12177A but not isoprenaline initiated arrhythmias at lower concentrations following beta(1)-adrenoceptor overexpression. 5. (125)I-Cyanopindolol saturation binding in Adv.beta(1) myocytes demonstrated approximately 18-fold increase in beta(1)-adrenoceptors. (3)H-CGP 12177A saturation binding, in the presence of propranolol, increased approximately 5-fold following overexpression of beta(1)-adrenoceptors. 6. This study demonstrates enhanced cardiostimulation by CGP 12177A (in the presence of propranolol) in rat ventricular myocytes overexpressing beta(1)-adrenoceptors, mediated by a Gs/cAMP signalling pathway. 'Putative' beta(4)-adrenoceptor pharmacology appears to be mediated by activation of a novel affinity state of the beta(1)-adrenoceptor.

Adrenergic beta-1 Receptor Agonists↗

PubMed1985

Effects of the calcium-channel agonist CGP 28392 on insulin secretion from isolated rat islets of Langerhans.

The rate of insulin secretion from isolated rat islets of Langerhans was affected by a number of dihydropyridine derivatives known to interact with voltage-sensitive Ca2+ channels in excitable cells. The channel antagonists nifedipine and nitrendipine were potent inhibitors of glucose-induced insulin secretion in response to both 8 mM- and 20 mM-glucose, although they did not lower the basal secretion rate observed in the presence of 4 mM-glucose. The Ca2+-channel agonist, CGP 28392, also failed to alter the basal rate of insulin secretion. In the presence of 8 mM-glucose, however, 1 microM-CGP 28392 enhanced the insulin-secretion rate to a value approximately double that with 8 mM-glucose alone. This effect was dose-dependent, with half the maximal response elicited by 0.1 microM-CGP 28392, and full enhancement at 10 microM. The response was rapid in onset, with an increase in insulin secretion evident within 2 min of CGP 28392 infusion in perifused islets. Stimulation of insulin secretion by CGP 28392 was correlated with a rapid enhancement of glucose-stimulated 45Ca2+ uptake into islets cells, and with a transiently increased rate of 45Ca2+ efflux from pre-loaded islets. Stimulation of insulin secretion by CGP 28392 was abolished in the presence of noradrenaline, although under these conditions the rapid stimulation of 45Ca2+ influx induced by CGP 28392 was only partially inhibited. In contrast with these results, when islets were incubated in the presence of 20 mM-glucose, CGP 28392 caused a dose-dependent inhibition of insulin secretion. Half-maximal inhibition required approx. 0.2 microM-CGP 28392, with maximal effects observed at 10 microM. Under these conditions, however, the extent of insulin secretion was still only decreased by about 50%, to a value which was similar to that seen in the presence of 8 mM-glucose and CGP 28392. These results suggest that dihydropyridine derivatives can alter the activity of voltage-dependent Ca2+ channels in islet cells, and are consistent with the possibility that gating of these channels plays an important role in regulating the rate of insulin secretion after glucose stimulation.

Animals↗

PubMed2003

Effects of two beta3-agonists, CGP 12177A and BRL 37344, on coronary flow and contractility in isolated guinea pig heart.

The functional role of beta(3)-adrenergic receptors in the heart is still not clear. The actions of two widely used beta(3)-adrenoceptor agonists, such as BRL 37344 and CGP 12177, were studied in the isolated guinea pig heart, perfused at constant pressure according to the Langendorff technique. Heart contractility (dP/dt, first derivative of pressure measured over time) and coronary flow (CF) were assessed simultaneously. BRL 37344 and CGP 12177A at a concentration range of 10-8-10-5 M increased dP/dt and CF. The selective beta(3)-antagonist L-748337 (10-6 M) did not significantly influence either BRL 37344 or CGP 12177A-induced responses. However, both dP/dt and CF responses to BRL 37344 and CGP 12177A at a concentration of 10-7 M were abolished in the presence of the beta(1)/beta(2)-antagonist nadolol (10-5 M). In contrast, cardiovascular responses to CGP 12177A at a higher concentration of 10-5 M were hardly inhibited by nadolol (10-5 M). In addition, BRL 37344 and CGP 12177A at concentrations as low as 10-8 M almost completely abolished an isoprenaline-induced increase in contractility, suggesting that both BRL 37344 and CGP 12177A display beta(1)-antagonistic properties. These data suggest that the stimulatory cardiovascular responses to BRL 37344 at a full range of concentrations, and CGP 12177A at a low concentration of 10-7 M, are not mediated by beta(3)-adrenergic receptors, but rather by activation of beta(1)- or beta(2)-adrenergic receptors. Cardiovascular effects of CGP 12177A at a high concentration of 10-5 M are independent of beta(1)/beta(2)/beta(3)-adrenergic receptors. Summing up, it seems that in the isolated guinea pig heart the functional role of beta(3)-adrenoceptors is not significant. Nonetheless, BRL 37344 and CGP 12177A are not ideal tools for investigation of beta(3)-adrenergic receptor-dependent effects, because these compounds interact with other types of beta-adrenergic receptors.

Adrenergic beta-1 Receptor Agonists↗

PubMed1996

Regionally different N-methyl-D-aspartate receptors distinguished by ligand binding and quantitative autoradiography of [3H]-CGP 39653 in rat brain.

1. Binding of D,L-(E)-2-amino-4-[3H]-propyl-5-phosphono-3-pentenoic acid ([3H]-CGP 39653), a high affinity, selective antagonist at the glutamate site of the N-methyl-D-aspartate (NMDA) receptor, was investigated in rat brain by means of receptor binding and quantitative autoradiography techniques. 2. [3H]-CGP 39653 interacted with striatal and cerebellar membranes in a saturable manner and to a single binding site, with KD values of 15.5 nM and 10.0 nM and receptor binding densities (Bmax values) of 3.1 and 0.5 pmol mg-1 protein, respectively. These KD values were not significantly different from that previously reported in the cerebral cortex (10.7 nM). 3. Displacement analyses of [3H]-CGP 39653 in striatum and cerebellum, performed with L-glutamic acid, 3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and glycine showed a pharmacological profile similar to that reported in the cerebral cortex. L-Glutamic acid and CPP produced complete displacement of specific binding with Ki values not significantly different from the cerebral cortex. Glycine inhibited [3H]CGP 39653 binding with shallow, biphasic curves, characterized by a high and a low affinity component. Furthermore, glycine discriminated between these regions (P < 0.005, one-way ANOVA), since the apparent Ki of the high affinity component of the glycine inhibition curve (KiH) was significantly lower (Fisher's protected LSD) in the striatum than the cortex (33 nM and 104 nM, respectively). 4. Regional binding of [3H]-CGP 39653 to horizontal sections of rat brain revealed a heterogeneous distribution of binding sites, similar to that reported for other radiolabelled antagonists at the NMDA site (D-2-[3H]-amino-5-phosphonopentanoic acid ([3H]-D-AP5) and [3H]-CPP). High values of binding were detected in the hippocampal formation, cerebral cortex and thalamus, with low levels in striatum and cerebellum. 5. [3H]-CGP 39653 binding was inhibited by increasing concentrations of L-glutamic acid, CPP and glycine. L-Glutamic acid and CPP completely displaced specific binding in all regions tested, with similar IC50 values throughout. Similarly, glycine was able to inhibit the binding in all areas considered: 10 microM and 1 mM glycine reduced the binding to 80% and 65% of control (average between areas) respectively. The percentage of specific [3H]-CGP 39653 binding inhibited by 1 mM glycine varied among regions (P < 0.05, two-ways ANOVA). Multiple comparison, performed by Fisher's protected LSD method, showed that the inhibition was lower in striatum (72% of control), with respect to cortex (66% of control) and hippocampal formation (58% of control). 6. The inhibitory action of 10 microM glycine was reversed by 100 microM 7-chloro-kynurenic acid (7-CKA), a competitive antagonist of the glycine site of the NMDA receptor channel complex, in all areas tested. Moreover, reversal by 7-CKA was not the same in all regions (P < 0.05, two-ways ANOVA). In fact, in the presence of 10 microM glycine and 100 microM 7-KCA, specific [3H]-CGP 39653 binding in the striatum was 131% of control, which was significantly greater (Fisher's protected LSD) than binding in the hippocampus and the thalamus (104% and 112% of control, respectively). 7. These results demonstrate that [3H]-CGP 39653 binding can be inhibited by glycine in rat brain regions containing NMDA receptors; moreover, they suggest the existence of regionally distinct NMDA receptor subtypes with a different allosteric mechanism of [3H]-CGP 39653 binding modulation through the associated glycine site.

2-Amino-5-phosphonovalerate↗

PubMed1985

A comparison of effects of BAY K 8644 and CGP 28392, dihydropyridines with Ca agonistic properties, on spontaneous mechanical activity in rat portal vein: modification of effect by ultraviolet radiation.

The effect of CGP 28392 and BAY K 8644 was studied on isolated portal veins from male Wistar Kyoto rats. BAY K 8644 and CGP 28392 induced a concentration dependent increase in spontaneous mechanical activity in low but not in high concentrations. The portal vein was more sensitive to the effect of BAY K 8644 than to that of CGP 28392. In Ca free medium the increasing effect of BAY K 8644 and CGP 28392 on the mechanical activity was abolished and restored by readdition of calcium. Nifedipine abolished the augmenting effect of BAY K 8644 and CGP 28392 on mechanical activity. Ultraviolet radiation (UVR) depressed the effect of BAY K 8644 but had no effect on mechanical activity induced by CGP 28392. BAY K 8644 and CGP 28392 degradate slowly under influence of UVR; BAY K 8644 was far more resistant to the destroying effect of UVR than CGP 28392. The results indicate that both BAY K 8644 and CGP 28392 increase the spontaneous mechanical activity in rat portal vein by enhancing Ca influx. The effect of BAY K 8644 differs from that of CGP 28392 by being sensitive to UVR; this action seems not to be due to a direct UVR destroying effect of the substances, but rather to a BAY K 8644 induced sensibilisation of the tissue to UVR.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1993

Safety and efficacy of recombinant hirudin (CGP 39 393) versus heparin in patients with stable angina undergoing coronary angioplasty.

BACKGROUND: Enhanced thrombin activity has been associated with acute and long-term complications following balloon angioplasty (percutaneous transluminal coronary angioplasty (PTCA). We evaluated, in a 2-to-1 randomized, double-blind trial, the effects of recombinant hirudin, CGP 39 393, relative to unfractionated sodium heparin on periprocedural events, bleeding, early angiographic outcome, and coagulation in 113 patients with stable angina undergoing PTCA. METHODS AND RESULTS: Prior to PTCA, 20 mg CGP 39 393 was administered as a bolus, followed by continuous infusion at a rate of 0.16 mg.kg-1 x h-1, or 10,000 IU sodium heparin was administered as a bolus and continued at a rate of 12 IU.kg-1 x h-1 for 24 hours. Infusion was adjusted to activated partial thromboplastin time (APTT) levels. ST segment was monitored for 24 hours, and angiograms were analyzed with quantitative technique (QCA). In 74 CGP 39 393- and 39 heparin-treated patients, 132 lesions were dilated. Myocardial infarction and/or emergency coronary bypass surgery occurred in 1 (1.4%) CGP 39 393 patient compared with 4 (10.3%) heparin patients (relative risk, 7.6; 95% confidence interval, 0.9, 65.6). At 24 hours, complete perfusion was present in 91% heparin and 100% CGP 39 393 patients. Significant ST segment displacement was found in 11% of heparin versus 4% of CGP 39 393 subjects. Bleeding occurred only at the puncture site in 4 CGP 39 393-treated patients. QCA did not reveal significant differences between the groups. APTT values were more often in the target range and more stable in CGP 39 393 patients. Levels of thrombin-antithrombin III complexes, prothrombin fragment F1+2, and fibrinopeptide A indicated that CGP 39 393 was an effective inhibitor of thrombin activity. CONCLUSIONS: CGP 39 393 can safely be administered to patients undergoing elective PTCA for stable anginal symptoms and may have a more favorable anticoagulant profile than heparin.

Aged↗

PubMedDate not supplied

Anomalous behavior of CGP 12177A on beta 1-adrenergic receptors.

CGP 12177A originally was developed as a hydrophilic antagonist to detect cell surface beta 1- and beta 2-adrenergic receptors, and subsequently was found to be a partial agonist for the atypical or beta 3-adrenergic receptor. Using hamster cells stably expressing either the human beta 1-, human beta 2- or rat beta 1-adrenergic receptor, we found that CGP 12177A behaved as an agonist of beta 1-adrenergic receptors. Whereas at low concentrations, CGP 12177a behaved as an antagonist and inhibited isoproterenol stimulation of adenylyl cyclase activity, at higher concentrations, it stimulated a response even in the absence of isoproterenol. The agonistic properties of CGP 12177A were positively correlated with the level of beta 1-adrenergic receptor expression. Thus, at low receptor of densities, CGP 12177A behaved as a weak, partial agonist whereas as high receptor densities, the drug was a full agonist. At similar high densities of the beta 2-adrenergic receptor, CGP 12177A acted only as a partial agonist. Competition binding studies to membranes from cells expressing beta 1-adrenergic receptors indicated that approximately 90% of the receptors were in a high affinity, guanine nucleotide-insensitive state for CGP 12177A whereas approximately 10% of the receptors were in a lower affinity, guanine nucleotide-sensitive state for CGP 12177A. We propose that the latter receptors are precoupled to stimulatory G proteins and recognize CGP 12177A as an agonist whereas the high affinity, uncoupled receptors recognize CGP 12177A as an antagonist.

1-Methyl-3-isobutylxanthine↗

PubMed1991

CGP 12177A modulates brown fat adenylate cyclase activity by interacting with two distinct receptor sites.

The interaction of [(-)-4-(3-t-butylamino-2-hydroxy-propoxy)benzimidazol-2-one] (CGP 12177) (CGP) with receptors that couple to adenylate cyclase was examined in membrane homogenates from rat interscapular brown adipose tissue (IBAT). Although typically regarded as a beta adrenoceptor antagonist, CGP stimulated adenylate cyclase activity with an activation constant of about 3 microM. Consistent with its classification as an antagonist, CGP inhibited norepinephrine-stimulated cyclase activity and did so at concentrations that had little or no stimulatory effect. CGP also inhibited activity stimulated by the atypical agonist [(R*,R*)-4-[2-[[2[(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]phenyl]phenoxyacetic acid (BRL 37344), but only at CGP concentrations that stimulated activity when tested alone. The beta-1-selective antagonist ICI 89,406 blocked norepinephrine-stimulated adenylate cyclase activity, but did not inhibit the activity stimulated by CGP. Together, these results indicate that CGP modulates IBAT adenylate cyclase by interacting with two receptors. One is the beta-1 receptor of which CGP is a high-affinity antagonist. The second appears to be an atypical receptor of which CGP is a partial agonist.

Adenylyl Cyclases↗

PubMed1997

Inhibition of cell growth: effects of the tyrosine kinase inhibitor CGP 53716.

The growth factors, platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) play major roles in enhanced smooth muscle cells growth in rodent blood vessels after vascular injury. Tyrosine kinase inhibition has been shown to be effective in blocking tyrosine phosphorylation at the PDGF and bFGF receptors in cultured fibroblast and vascular smooth muscle cells which in turn inhibits their proliferation. Our study evaluated the PDGF selective tyrosine kinase inhibitor, CGP 53716, on serum, PDGF-BB, bFGF or epidermal growth factor-induced growth responses in cultured rat aortic smooth muscle cells (RASMC) and Balb/3T3 fibroblasts (3T3). CGP 53716 inhibited serum-induced cell growth in RASMC, but not in 3T3 cells. CGP 53716 completely blocked PDGF-BB tyrosine receptor autophosphorylation in RASMC and 3T3 cells, PDGF-BB-induced phosphorylation of mitogen-activated protein kinase at 1 microM in RASMC and inhibited PDGF-BB-induced c-Fos protein expression at 1 microM in RASMC; consistent with inhibition of PDGF-BB-induced DNA synthesis. To examine the selectivity of CGP 53716, PDGF-BB, bFGF or EGF-induced DNA synthesis was measured using thymidine incorporation. CGP 53716 inhibited PDGF-BB-, bFGF- and EGF-induced DNA synthesis in a concentration-dependent manner in each cell line. CGP 53716 showed a 2- to 4-fold selectivity for PDGF-BB-stimulated DNA synthesis over bFGF or EGF in RASMC or 3T3 cells. To rule out that bFGF induced the release of endogenous PDGF, an antibody to PDGF-AB, which binds to all three isoforms of PDGF, was coincubated with bFGF and did not suppress the DNA synthesis induced by bFGF. Based on these results, CGP 53716 is not selective for the PDGF receptor as previously reported. However, EGF-stimulated receptor autophosphorylation of mitogen-activated protein kinase phosphorylation and c-Fos protein expression were not inhibited by CGP 53716 at 1 or 10 microM in RASMC. These findings suggest that CGP 53716 may inhibit multiple growth factor pathways as indicated by inhibition of DNA synthesis. However, these effects must be downstream from the signaling for c-Fos protein expression or use an alternate signaling route. These results further suggest that CGP 53716 may have a therapeutic potential for the treatment of vascular proliferative diseases which are stimulated by not only PDGF but other growth factors such as bFGF and EGF.

3T3 Cells↗

PubMed1988

Effects of the thiazolidinedione derivative CGP 19984 on growth and endocrine function of the MtT-W10 transplantable mammosomatotropic pituitary tumor in female rats.

The thiazolidinedione derivative CGP 19984 has previously been shown to suppress the growth of hormone-dependent mammary and prostatic tumors, primarily by reducing gonadotropin and subsequently gonadal steroid secretion. The present study examines the effects of CGP 19984 on the growth and hormone secretion of the autonomous, but estrogen-responsive, MtT-W10 mammosomatotropic transplantable rat pituitary tumor. Intact tumor-bearing Wistar/Furth female rats were administered vehicle or 25, 100, or 250 mg/kg CGP 19984 p.o., 5 x week for 4 weeks. CGP 19984 was found to significantly reduce MtT-W10 tumor growth and weight and reduce prolactin and growth hormone (GH) secretion in a dose-responsive manner. A similar study in ovariectomized rats also showed that CGP 19984 treatment suppressed MtT-W10 pituitary tumor growth, weight and hormone secretion in a dose-responsive manner, suggesting a direct inhibitory action of this drug on the tumor. In a third study, bromocryptine (CB-154; 5 mg/kg) and CGP 19984 (50 mg/kg) were both found to be effective in suppressing growth of the MtT-W10 tumor in intact female rats. However, rats treated with CGP 19984 alone had reduced serum and tumor GH and prolactin concentrations, while rats treated with CB-154 alone had reduced serum and tumor prolactin, but no change in GH concentrations. These results suggest that CGP 19984 effectively inhibits growth and hormone secretion of the autonomous MtT-W10 pituitary tumor by apparently suppressing both somatotropic and lactotropic cell populations within the tumor. Furthermore, these findings indicate that CGP 19984 may be an effective alternative to CB-154 in the clinical treatment of prolactin-producing adenomas, as well as other types of pituitary adenomas.

Animals↗

PubMed2002

(-)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the beta 1-adrenoceptor.

Two forms of the activated beta1-adrenoceptor exist, one that is stabilized by (-)-noradrenaline and is sensitive to blockade by (-)-propranolol and another which is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is relatively insensitive to (-)-propranolol. We investigated the effects of stimulation of the propranolol-resistant beta1-adrenoceptor in the human heart. Myocardium from non-failing and failing human hearts were set up to contract at 1 Hz. In right atrium from non-failing hearts in the presence of 200 nM (-)-propranolol, (-)-CGP 12177 caused concentration-dependent increases in contractile force (-logEC50[M] 7.3+/-0.1, E(max) 23+/-1% relative to maximal (-)-isoprenaline stimulation of beta1- and beta2-adrenoceptors, n=86 patients), shortening of the time to reach peak force (-logEC50[M] 7.4+/-0.1, E(max) 37+/-5%, n=61 patients) and shortening of the time to reach 50% relaxation ( t(50%), -logEC50[M] 7.3+/-0.1, E(max) 33+/-2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-beta1-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (-logEC50[M] 7.7+/-0.1, E(max) 68+/-6%, n=6 patients, P<0.0001). In the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine, the potency (-logEC50[M] 7.4+/-0.1, P=0.0013, n=9 patients) but not the maximal effect of (-)-CGP 12177 was reduced in right atrium from failing hearts, which was associated with 64% and 52% reductions in the densities of low-affinity and high-affinity (-)-[3H]CGP 12177 binding sites. In the presence of (-)-propanolol and 3-isobutyl-1-methylxanthine, (-)-CGP 12177 increased atrial cyclic AMP levels and activated cyclic AMP-dependent protein kinase in right atrium from non-failing hearts. In right ventricle from failing hearts (-)-CGP 12177 increased contractile force (-logEC50[M] 7.4+/-0.1, E(max) 34+/-3%, n=13 patients) and hastened the time to peak force (-logEC50[M] 7.6+/-0.1) and time to reach 50% relaxation (-logEC50[M] 7.4+/-0.1) in the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine. Our results show that (-)-CGP 12177 increases contractility and hastens relaxation through a cyclic AMP pathway in human myocardium, consistent with mediation through a (-)-propranolol-resistant state of the beta1-adrenoceptor. The reduction in heart failure of atrial inotropic potency of (-)-CGP 12177, as well as of the high-affinity and low-affinity binding sites for (-)-[3H]CGP 12177, is consistent with the beta1-adrenoceptor nature of these sites.

Adrenergic beta-1 Receptor Agonists↗

PubMed1987

Effects of calcium channel activators BAY-K8644 and CGP-28392 on steroidogenesis in granulosa cells of the domestic hen.

The effects of calcium agonists BAY-K8644 and CGP-28392 on steroidogenesis was examined in chicken granulosa cells in short term incubation. BAY-K8644 (5-500 nM) and low doses of CGP-28392 (1-10 microM) failed to appreciably affect basal and LH-stimulated progesterone production whether tested in calcium free, low (0.05 mM) or high (3 mM) calcium containing medium. However, higher concentrations of CGP-28392 (50-250 microM) inhibited significantly (P less than 0.01) both basal and LH-stimulated steroidogenesis in a dose-related manner independently of extracellular calcium availability. The suppressive effect of CGP-28392 was manifest with submaximally and maximally stimulating LH doses. In additional experiments with non-hormonal agonists such as forskolin, dibutyryl cyclic AMP and kaurenol, BAY-K8644 and low CGP-28392 concentrations were again without effect on steroidogenesis. By comparison, higher CGP-28392 doses suppressed the stimulatory effects of all three agonists dose-dependently. These results demonstrate that, the calcium channel agonists are incapable of inducing a steroidogenic response in chicken granulosa cells. Since BAY-K8644 and CGP-28392 (low dose, 1-10 microM) failed to influence steroidogenesis in the dose range that induced maximal physiologic responses and calcium influx in a variety of cells, it is concluded that chicken granulosa cells lack the type(s) of channels specific for them. Hence the usefulness of BAY-K8644 and CGP-28392 as Ca2+ probes may be tissue-specific. The inhibitory effects of CGP-28392 appear to be non-specific.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2006

Inhibition of L-type Ca2+ channel by mitochondrial Na+-Ca2+ exchange inhibitor CGP-37157 in rat atrial myocytes.

7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepine-2(3H)-one (CGP-37157) inhibits mitochondrial Na(+)-Ca(2+) exchange. It is often used as an experimental tool for studying the role of the mitochondrial Na(+)-Ca(2+) exchanger in Ca(2+) signaling. Because the selectivity of CGP-37157 in adult cardiomyocytes has not been confirmed, we tested whether CGP-37157 affects the L-type Ca(2+) channel using a whole-cell patch-clamp in adult rat atrial myocytes. We found that CGP-37157 suppressed L-type Ca(2+) current (I(Ca)) with IC(50) of approximately 0.27 microM, without altering the voltage dependence of the current-voltage relationships. CGP-37157 inhibited the Ba(2+) current (I(Ba)) through the Ca(2+) channel with a similar dose-response. The inhibitory effects of CGP-37157 on I(Ca) or I(Ba) were resistant to the intracellular Ca(2+) buffering. Intracellular application of CGP-37157 did not significantly alter I(Ca). The combination of CGP-37157 with known Ca(2+) channel inhibitor diltiazem yielded antagonism consistent with additivity of response. Our data suggest that CGP-37157 directly suppresses the L-type Ca(2+) channel in intact adult cardiomyocytes.

Animals↗

PubMed2006

Mercaptoacetate fails to block the feeding-inhibitory effect of the beta3-adrenergic receptor agonist CGP 12177A.

Peripherally administered beta3-adrenergic receptor (beta3-AR) agonists stimulate lipolysis and inhibit food intake. To test the hypothesis that this inhibition of feeding is due to a substrate-driven increase in hepatic fatty acid oxidation (FAO), we assessed the ability of the FAO inhibitor mercaptoacetate (MA) to reverse the feeding-inhibitory effect of the beta3-AR agonist CGP 12177A (CGP). Adult male Sprague-Dawley rats received intraperitoneal injections of 1 mg/kg CGP, of 45.6 mg/kg MA, or of both drugs, and the effects on food intake, plasma free fatty acids (FFA), and plasma beta-hydroxybutyrate (BHB), an indicator for hepatic FAO, were assessed. Control rats received saline injections. CGP significantly reduced food intake after 0.5 and 6 h and increased plasma FFA and BHB at 0.5 h, suggesting increased lipolysis and hepatic FAO. MA completely reversed the increase in plasma BHB and thus appeared to effectively abolish CGP's effect on hepatic FAO, but MA failed to affect CGP's feeding-inhibitory action. These findings do not support the hypothesis that the beta3-AR agonist CGP inhibits feeding by enhancing hepatic FAO or ketogenesis. Although the beta3-AR agonist CGP reduced saccharin intake in a one-bottle condition taste aversion test, it seems unlikely that the hypophagic effect of CGP is elicited by malaise.

3-Hydroxybutyric Acid↗

PubMed1997

Selective block of N-methyl-D-aspartic acid (NMDA)-evoked whole-cell currents in mouse cultured spinal neurones by CGP 40116.

1. CGP 40116 is the active (R)-enantiomer of the most potent N-methyl-D-aspartic acid (NMDA) receptor antagonist presently available: 2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849). In this study, we describe the effect of CGP 40116 on whole-cell currents induced by excitatory amino acids in cultured mouse spinal cord cells by use of the whole-cell patch-clamp technique. 2. We found that application of CGP 40116 in the nM range, concentration-dependently inhibited whole-cell current evoked by 20 microM NMDA in mouse cultured spinal neurones (IC50 +/- s.e. mean 48 +/- 8 nm CGP 40116). 3. The compound appeared to be highly selective for the NMDA current. At concentrations as high 1 microM, currents evoked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or kainic acid were not affected by CGP 40116. The threshold concentration for antagonism of NMDA-induced responses was 10 nM suggesting a selectivity ratio of > or = 100 fold for NMDA receptors versus AMPA or kainate receptors. 4. CGP 40116 produced a parallel rightward displacement of the NMDA log concentration-current curve indicating competitive antagonism at the transmitter recognition site of the NMDA receptor complex. An apparent dissociation constant for the antagonist was calculated from the displacement of the agonist concentration-current curve: 117 +/- 53 nM CGP 40116 (estimated Kd +/- s.e.). Like other competitive NMDA antagonists, CGP 40116 blocked NMDA-evoked current in a voltage-independent manner.

2-Amino-5-phosphonovalerate↗

PubMed1995

Neuroprotection by the N-methyl-D-aspartate receptor antagonist CGP 40116: in vivo and in vitro studies.

The goal of this study was to evaluate the effects of a novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist, D-(E)-2-amino-4-methyl-5-phosphono-3-pentoic acid (CGP 40116), on neuronal damage in vivo and in vitro. We studied 20 rabbits that underwent a 2-h occlusion of the left internal carotid, anterior cerebral, and middle cerebral arteries followed by 4 h of reperfusion. Ten minutes after occlusion the animals were treated with either normal saline (n = 7) or CGP 40116 at two different doses (20 mg/kg, n = 6; 40 mg/kg, n = 7) administered over a 5-min period. Somatosensory evoked potentials were used to confirm adequate ischemia and neuronal injury was assessed by histopathology and magnetic resonance imaging. CGP 40116 decreased cortical ischemic neuronal damage by 74 and 77% (control, 37.8 +/- 13.1%; CGP 20 mg/kg, 9.9 +/- 3.6%; CGP 40 mg/kg, 8.7 +/- 3.7%; p < 0.01) and reduced cortical ischemic edema by 52 and 35% (control, 42.3 +/- 10.4%; CGP 20 mg/kg, 20.1 +/- 6.7%; CGP 40 mg/kg, 27.5 +/- 13.3%; p < 0.05) but did not protect against striatal injury. We performed a second study using primary cell cultures from mouse neocortex to determine the effects of CGP 40116 on neuronal death induced by a 10-min exposure to 500 microM NMDA or by 45 min of oxygen-glucose deprivation (OGD). Our results demonstrate that CGP 40116 was effective at attenuating neuronal death in a concentration-dependent manner (ED50 of 3.2 microM against NMDA toxicity and 23.1 microM against OGD) as measured by lactate dehydrogenase levels 24 h after the insult.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗

PubMed1994

Effect of the competitive NMDA antagonist, CGP 40 116, and a low dose of l-Dopa on the motor activity deficit of MPTP-treated mice.

Three experiments were performed to investigate the effects of combining the active D-stereoisomer of CGP 37 849, i.e. the glutamatergic antagonist, CGP 40 116, with l-dopa, in mice that had undergone treatment with the neurotoxin, MPTP. In the first experiment, the decreased motor activity in MPTP-treated mice was alleviated by the administration of a low dose of l-dopa (5mg/kg, s.c.) together with a low dose of CGP 40 116 (30µg/kg). This dose was inactive in the control (saline-treated) mice. The highest dose of CGP 40 116 used (3000µg/kg) stimulated activity in the control mice. In Experiment 2, the inactive L-stereoisomer, i.e., CGP 40 117, was found to be inactive at doses (3 and 30µg/kg) effective with CGP 40 116. The effects of CGP 40 116 and l-dopa on the 24-h activity of mice tested under either day-night or night-day conditions, were more marked and longer lasting in the night-day condition. Taken together, the results from all three experiments show that CGP 40 116 in a dose range of 1-30µg/kg in combination with l-dopa (5mg/kg, s.c.) alleviated the reduced motor activity in MPTP-treated mice whereas higher doses of CGP 40 116 (100, 300, or 3000µg/kg) or lower doses (0.1 and 0.3µg/kg) were without effect. These experiments are interpreted as support for current views on glutamatergic-dopaminergic interactions in Parkinsonism and offer further evidence for the MPTP mouse model of the disease.

Journal Article↗

PubMed1990

Pharmacokinetics of CGP 6140 (amocarzine) after oral administration of single 100-1600 mg doses to patients with onchocerciasis.

The concentrations of CGP 6140 [4-nitro-4'-(N-methyl-piperazinylthiocarbonylamido)-diphenylamine] and of its N-oxide metabolite, CGP 13,231, were measured in plasma and urine after single oral dose of 100-1600 mg of CGP 6140 to 41 fasted Ghanaian patients with Onchocerca volvulus infections. The absorption of CGP 6140 was rapid and its terminal elimination half-life was about 3 h. The plasma concentrations of CGP 6140 were essentially proportional to the dose. A greater variability in plasma concentrations was apparent after the 800 and 1600 mg doses indicating a poor bioavailability of the drug administered in fasting conditions to several patients. In plasma, the concentrations of CGP 13,231 were similar to those of CGP 6140. The amount of CGP 13,231 excreted in urine was 25-40% of the dose of CGP 6140 whereas only 1.5% was excreted as unchanged drug. If a single dose of drug is used for the treatment, the plasma concentration would be maintained for 3-4 h at a high level. At 8 h, the concentration falls to about 10% of the Cmax. If sustained plasma concentrations of the drug are needed for efficacy, twice daily administration would maintain the minimum concentration at about 10% of the Cmax.

Chromatography, High Pressure Liquid↗