SEARCH · PubMed Health

Results for “CGP”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMedDate not supplied

Anticonvulsant activity of two orally active competitive N-methyl-D-aspartate antagonists, CGP 37849 and CGP 39551, against sound-induced seizures in DBA/2 mice and photically induced myoclonus in Papio papio.

Two novel N-methyl-D-aspartate (NMDA) antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid CPG 37849 and the corresponding 1-ethyl ester CGP 39551, were tested as anticonvulsants in DBA/2 mice and photosensitive Senegalese baboons, Papio papio. In DBA/2 mice, CGP 37849 is more potent than CGP 39551 when administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) (ED50 for suppression of clonic seizures at 60 min: i.c.v. 0.038 and 0.21 nmol; i.p. 3.40 and 19.1 mumol/kg, respectively). When administered orally in mice, the two compounds are approximately equipotent (ED50 CGP 37849, 35.2 mumol/kg; ED50 CGP 39551, 28.1 mumol/kg). The time course of action of CGP 39551 is exceptionally prolonged: 42 mumol/kg i.p. protects against clonic seizures for 48 h. Protection provided by other NMDA antagonists in mice is of much shorter duration: 2-amino-5-phosphono-pentanoic acid (AP5) 1 h, 2-amino-7-phosphono-heptanoic acid (AP7) 4 h, 2-amino-7-phosphono-heptanoic acid 1-ethyl ester 3 h, 4-(3-phosphonopropyl)-2-piperazine carboxylic acid (CPP) 2 h, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) 4 h, and CGP 37849 4 h. After oral administration of the drugs, the therapeutic index (TI = ratio of the ED50 values for rotorod performance and anticonvulsant protection) remains relatively constant at 5.9-7.2 for 3 h (CGP 37849) and 4.0-6.1 for 24 h (CGP 39551). After i.p. administration, the TI values are CGP 37849 at 1 h 2.4, and at 3 h 20.0, CGP 39551 at 1 h 2.3, at 3 h 7.1, and at 24 h 3.6. In baboons, acute administration of CGP 37849 at doses of 48-191 mumol/kg intravenously (i.v.) suppresses photically induced myoclonus for at least 285 min, with severe side effects at the highest dose tested. CGP 39551 at doses of 169-675 mumol/kg i.v. shows weak anticonvulsant activity only at the highest dose tested (accompanied by severe side effects). CGP 37849 at 48-96 mumol/kg orally (p.o.) fails to protect against photically induced myoclonus up to 4 h after administration, but 191 mumol/kg (40 mg/kg) p.o. produces complete suppression of seizures after 24 h. On the other hand, CGP 39551 at 169 mumol/kg (40 mg/kg) p.o. produces total suppression of seizure activity at 4 h with a longer duration of anticonvulsant action (2-3 days).(ABSTRACT TRUNCATED AT 400 WORDS)

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Influence of staurosporine, a more selective derivative CGP 41,251 and an inactive analogue CGP 42,700 on histamine release from isolated rat mast cells.

The influence of staurosporine, a potent but nonselective inhibitor of protein kinase C, on rat mast cell histamine release, was compared with that of two derivatives, CGP 41,251 with a high degree of selectivity for protein kinase C and the related CGP 42,700 which is without activity. Staurosporine was a more potent inhibitor of mast cell responses than CGP 41,251, in accordance with their reported potencies. CGP 42,700 was investigated in the same concentration range as CGP 41,251 and served as a control for unspecific effects. Antigen induced histamine release was more effectively inhibited by staurosporine than by CGP 41,251, and responses to compound 48/80 were only modestly affected by both drugs. Responses to the ionophore A23187 were unaffected by staurosporine whereas CGP 41,251 was an effective inhibitor at suboptimal ionophore concentrations. In contrast, responses to combinations of the phorbol ester TPA and subthreshold concentrations of the ionophore could be potently inhibited by staurosporine but were under certain conditions moderately enhanced by lower concentrations of the drug, whereas CGP 41,251 was only inhibitory. Except for a slight inhibition of ionophore responses CGP 42,700 was without effect. The results demonstrate that the actions of staurosporine cannot be ascribed solely to inhibition of protein kinase C, whereas the influence of CGP 41,251 appears to be consistent with an inhibition of this kinase.

Alkaloids↗

PubMed1992

Suitability of CGP-12177 and CGP-26505 for quantitative imaging of beta-adrenoceptors.

[3H]CGP-12177, a non-selective beta-adrenoceptor antagonist, and [3H]CGP-26505, a beta 1-selective beta-adrenoceptor antagonist, were intravenously administered to rats. 94-97% of the injected radioactivity disappeared from plasma with t1/2 0.2 and 0.5 min. Total/non-specific binding ratios of 5.4 and 6.9 (CGP-12177) or 2.0 and 2.8 (CGP-26505) were maintained in heart and lung from 10 to 40 min post-injection. Labelled plasma metabolites appeared after greater than 20 min (CGP-12177) or within 2 min (CGP-26505). No metabolites were found in the heart. CGP-12177 binds to blood cells, but CGP-26505 does not. CGP-12177 can be used for PET imaging of total (beta 1 and beta 2) adrenoceptors in the heart and lung of experimental animals, but CGP-26505 is less suitable for in vivo analysis of the beta 1-subpopulation.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

The effect of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, in the forced swimming test.

The present study examined the effects of CGP 37849 and CGP 39551, competitive NMDA receptor antagonists, in the forced swimming test in rats and mice. Administered in a single dose or three times both examined compounds reduced the immobility time in rats. Active doses used in that test either did not change the locomotor activity or decreased it. A similar effect in both tests was shown by active (R)-enantiomers CGP 40116 and CGP 43487. Reduction of the immobility time induced by CGP 37849 and CGP 39551 in the forced swimming test in rats was antagonized by haloperidol and (+/-)-sulpiride, but not by SCH 23390 or prazosin. CGP 37849, but not CGP 39551, also reduced the immobility time in the forced swimming test in mice. The results obtained indicate that CGP 37849 and CGP 39551 induce an antidepressant-like effect in the forced swimming test, probably via an indirect dopamine activation resulting from blockade of NMDA receptors.

2-Amino-5-phosphonovalerate↗

PubMed1991

Anticonvulsant and behavioral effects of two novel competitive N-methyl-D-aspartic acid receptor antagonists, CGP 37849 and CGP 39551, in the kindling model of epilepsy. Comparison with MK-801 and carbamazepine.

The orally active competitive N-methyl-D-aspartate (NMDA) receptor antagonists CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) and its ethyl ester CGP 39551 were evaluated in amygdala-kindled rats, a model for complex partial and secondarily generalized seizures. Anticonvulsant and behavioral effects of these novel compounds were compared with those of the noncompetitive NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e] and the antiepileptic drug carbamazepine, one of the major drugs for treatment of partial and generalized seizures in humans. For comparative evaluation, the compounds were injected i.p. at the following doses: 1 to 10 mg/kg (CGP 37849 or CGP 39551), 0.05 to 0.3 mg/kg (MK-801) and 20 to 40 mg/kg (carbamazepine), respectively. In contrast to carbamazepine, CGP 37849, CGP 39551 and MK-801 exerted only weak anticonvulsant effects in fully kindled rats and did not increase the focal seizure threshold. The weak anticonvulsant effects of the NMDA receptor antagonists in kindled rats were associated with profound untoward behavioral effects. The behavioral syndrome induced by the NMDA receptor antagonists in kindled rats was characterized by marked ataxia, hyperactivity and, in case of CGP 37849 and MK-801, stereotypies, such as head weaving. The low or absent effectiveness of the novel NMDA receptor antagonists against kindled seizures suggests that these compounds will not be clinically useful antiepileptics against partial and secondarily generalized seizures. Furthermore, in view of the recent clinical findings on psychotomimetic effects of MK-801 in epileptic patients, the similarities in the excitatory effects produced by CGP 39551, CGP 37849 and MK-801 in kindled rats may indicate that competitive NMDA receptor antagonists may also produce psychotomimetic effects in humans.

2-Amino-5-phosphonovalerate↗

PubMed1992

Immunotherapy of murine renal adenocarcinoma by systemic administration of liposomes containing the synthetic macrophage activator CGP 31362 or CGP 19835A in combination with interleukin 2 or gamma-interferon.

The purpose of these experiments was to evaluate the possibility that the systemic administration of liposomes containing synthetic macrophage activation CGP 31362 or CGP 19835 in mice which were simultaneously receiving injections of gamma-interferon or interleukin 2 would lead to enhanced regression of spontaneous lung metastases produced by syngeneic renal adenocarcinoma. The kidneys of BALB/c mice were given injections of renal adenocarcinoma cells, and 10 days later the kidney with local tumor was surgically resected. These mice were then given injections i.v. with liposomes and with gamma-interferon (s.c.) or interleukin 2 (i.p.). Systemic administration of MLV-CGP 31362 and MLV-CGP 19835A significantly reduced the number of lung metastases in nephrectomized mice. Both lung tumor burden and regional recurrence were further reduced by the s.c. injection of gamma-interferon or i.p. injection of interleukin 2. Long-term survivors were observed only in the groups of animals treated with liposomes containing macrophage activators and with lymphokines. Evaluation of host responsiveness to this immunotherapy revealed in situ activation of alveolar macrophages by administration of MLV-CGP 31362 or MLV-CGP 19835A, which was enhanced in mice also treated with interleukin 2. Normal levels of natural killer cell activity were reduced in the spleens of tumor-bearing mice but were restored subsequent to treatment with MLV-CGP 31362. These results indicate the potential usefulness of treating metastatic renal cell carcinoma by systemic administration of liposomes containing synthetic macrophage activators in combination with parental injections of lymphokines.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1992

Weak anticonvulsant activity of CGP 37849 and CGP 39551 against kindled seizures following systemic administration.

The anticonvulsant and behavioural actions of CGP 37849 and CGP 39551, two novel competitive NMDA receptor antagonists, were examined in fully amygdala kindled rats following systemic administration. Only weak anticonvulsant effects were observed following either i.p. or i.v. injection of the antagonists. Moreover, behavioural abnormalities (ataxia, hyperactivity, muscular hypotonia) were apparent at all anticonvulsant doses. These results suggest that CGP 37849 and CGP 39551 may be of limited therapeutic usefulness against complex partial seizures in man, the seizure type showing greatest refractoriness to presently available medication.

2-Amino-5-phosphonovalerate↗

PubMed1992

Uptake of radioligands by rat heart and lung in vivo: CGP 12177 does and CGP 26505 does not reflect binding to beta-adrenoceptors.

The biodistribution of (-)-4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H-benzimidazol-2-one (CGP12177, a non-selective beta-adrenoceptor antagonist) and 1-[2-(3-carbamoyl-4-hydroxy)-(5-3H-phenoxy)]-2-propanol methanesulfonate, (CGP26505, a beta 1-adrenoceptor antagonist) was studied in rats pretreated with various alpha- and beta-adrenoceptor blocking drugs (5 min before 3H injection, in dosages at which the drugs demonstrated the expected selectivity). Cardiac and pulmonary radioactivity were measured after 10 min, when specific binding was maximal. Uptake of [3H]CGP12177 was linked to binding to beta-adrenoceptors since it was not affected by prazosin or yohimbine, and was equally well inhibited by propranolol, unlabelled CGP12177 and isoprenaline. Moreover, atenolol and CGP20712A inhibited [3H]CGP12177 uptake in heart (predominantly beta 1-adrenoceptors) more potently than ICI 118,551, while in lungs (predominantly beta 2-adrenoceptors) ICI 118,551 was more potent than atenolol or CGP20712A. In contrast, [3H]CGP26505 uptake in the target organs was equally effectively inhibited by propranolol and ICI 118,551, and significantly lowered by alpha-adrenoceptor antagonists. We conclude that [11C]CGP12177, but not [11C]CGP2605 will be suitable for positron emission tomography imaging of beta-adrenoceptors in animals.

Adrenergic alpha-Antagonists↗

PubMed1991

Adenylate cyclase agonist properties of CGP-12177A in brown fat: evidence for atypical beta-adrenergic receptors.

Thermogenesis in brown adipose tissue (BAT) is stimulated by catecholamine activation of adenylate cyclase through the beta-adrenergic receptor. Recently it was reported that the beta-adrenergic antagonist CGP-12177A stimulates oxygen consumption in BAT. To investigate the mechanism of action of CGP-12177A in BAT, we assessed the inhibitory and stimulatory affects of CGP-12177A on the adenylate cyclase system in myocardial and BAT membranes from rats. CGP-1277A inhibited isoproterenol-stimulated adenylate cyclase activity in a dose-dependent manner, with an inhibitory constant (Ki) of 1.94 +/- 0.18 microM in BAT and 0.49 +/- 0.11 microM in the heart. However, in the absence of isoproterenol, CGP-12177A stimulated adenylate cyclase in BAT with two components of activation, and half-maximal stimulation occurred at 1 microM and 1.5 mM. In contrast, CGP-12177A did not stimulate adenylate cyclase activity in heart membranes. Propranolol inhibited the isoproterenol-stimulated activity with a potency that was one log less in BAT compared with heart. Propranolol fully blocked the high-affinity component but only weakly blocked the low-affinity component of CGP-12177A-stimulated activity in BAT. Pindolol was also less potent in BAT but inhibited the CGP-12177A-stimulated activity in a manner similar to the inhibition of the isoproterenol-stimulated activity, suggesting the CGP-12177A activation was beta-receptor mediated. Binding curves of [125I]iodocyanopindolol ([125I]ICYP) in competition with CGP-12177A demonstrated a shift to lower affinity in the presence of beta,gamma-imidoguanosine 5'-triphosphate, indicating that CGP-12177A has agonist properties with respect to the [125I]ICYP binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗

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↗

PubMed1991

The novel competitive N-methyl-D-aspartate (NMDA) antagonist CGP 37849 preferentially induces phencyclidine-like behavioral effects in kindled rats: attenuation by manipulation of dopamine, alpha-1 and serotonin1A receptors.

The novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) was found to produce a phencyclidine (PCP)-like behavioral syndrome (ataxia, locomotion, stereotypies) in amygdala-kindled rats, whereas the amphetamine-like behavioral alterations of the syndrome (locomotion, stereotypies) were only infrequently seen in nonkindled rats. In dose-response experiments in kindled and nonkindled rats, behavioral effects were scored using a ranked intensity scale, and the behaviors and behavioural scores determined after CGP 37849 were compared with those determined after i.p. administration of the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801). In kindled rats, 20 mg/kg of CGP 37849 produced about the same scores for hyperlocomotion and head weaving as 0.1 mg/kg of MK-801. Kindled rats exhibited higher behavioral scores than nonkindled rats, especially in the case of CGP 37849. The behavioral effects produced by CGP 37849 in kindled rats were almost indistinguishable from the PCP-like behavioral effects induced by MK-801, indicating that CGP 37849 indeed produces a PCP-like pattern of behavior in kindled rats. Hyperlocomotion and head weaving induced by CGP 37849 in kindled rats could be attenuated or totally prevented by pretreatment with ipsapirone, a partial agonist/antagonist at postsynaptic 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype. Furthermore, these behavioural effects were attenuated or blocked by the dopamine antagonist haloperidol and the alpha-1 adrenoceptor antagonist, prazosin. The data demonstrate that kindling induces a hypersensitivity to PCP-like behavioral effects of competitive and noncompetitive NMDA receptor antagonists, which could relate to the recent finding of increased function of NMDA receptors following kindling.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗

PubMed1991

Studies on pituitary melanotrophs reveal the novel GABAB antagonist CGP 35-348 to be the first such compound effective on endocrine cells.

One obstacle to understanding the action and physiological significance of the responsiveness of various endocrine cells to gamma-aminobutyric acid (GABA) has been that previously available substances, all active as GABAB antagonists in the nervous system, are ineffective on endocrine cells. The introduction of a potent new member of this class, CGP 35-348, of very different chemical structure, encouraged us to examine its effect on endocrine cells. For this purpose, we studied melanotroph secretion from pituitary neurointermediate lobes. We found that CGP 35-348, in contrast to previously available members of this class, suppressed completely, in rat and toad, secretory responses to baclofen, the classic GABAB agonist. Analysis, in toad, showed CGP 35-348 did not affect responses to GABAA agonists (muscimol; isoguvacine), dopamine, or neuropeptide Y. When tested against GABA, the physiological ligand present in the innervation of melanotrophs (along with dopamine and neuropeptide Y), CGP 35-348 completely suppressed the secretory response, which, in toad, is purely inhibitory and unaffected by bicuculline, the specific GABAA antagonist. In addition, CGP 35-348 unmasked a stimulant effect that bicuculline blocked. In CGP 35-348, we thus have a new tool with which to analyse responses to GABA and their physiological involvement in endocrine cells.

Animals↗

PubMed1991

CGP 35348, a new GABAB antagonist, prevents antinociception and muscle-relaxant effect induced by baclofen.

1. CGP 35348, a new GABAB antagonist, was examined on antinociception induced by (+/-)-baclofen by use of the hot plate and writhing tests in mice and the paw pressure test in rats. CGP 35348 was also studied in mice on (+/-)-baclofen-induced impairment of rota-rod performance. 2. CGP 35348, injected either i.p. (60-100 mg kg-1 in mouse) or intracerebroventricularly (i.c.v.) (0.5-2.5 micrograms per mouse; 25 micrograms per rat) prevented (+/-)-baclofen-induced antinociception. 3. CGP 35348 did not modify oxotremorine- and morphine-induced antinociception in mice and rats. 4. CGP 35348 (2.5 micrograms i.c.v. per mouse) also prevented (+/-)-baclofen-induced impairment of the rota-rod test. 5. Two other GABAB antagonists, phaclofen (50 micrograms i.c.v. per mouse) and 2-OH-saclofen (2.5 micrograms-10 micrograms i.c.v. per mouse) did not modify (+/-)-baclofen-induced antinociception. 7. These results suggest that, at present, CGP 35348 is the only compound able to antagonize (+/-)-baclofen-induced antinociception.

Analgesics↗

PubMed1992

The positive chronotropic effect induced by BRL 37344 and CGP 12177, two beta-3 adrenergic agonists, does not involve cardiac beta adrenoceptors but baroreflex mechanisms.

The presence of a beta-3 adrenoceptor (in addition to the classical beta-1 and beta-2 adrenoceptors) and its involvement in the control of heart rate was investigated in the dog. Experiments were carried out in conscious normal and sinoaortic denervated dogs (i.e. animals deprived of baroreceptor pathways). In normal dogs, infusion of isoproterenol, BRL 37344 (4-[-[(2-hydroxy-(3-chlorophenyl) ethyl)-amino]propyl]phenoxyacetate) (a beta-3 adrenergic agonist) or CGP 12177 (4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2- one) (a beta-1 beta-2 adrenergic antagonist reported to act as an agonist for the beta-3 adrenergic receptor) increased heart rate with an order of potency: BRL 37344 > isoproterenol >> CGP 12177. [125I]Cyanopindolol binding (2-2000 pM) was saturable and Scatchard analysis indicated the presence of an homogenous population of binding sites. KD was 12.8 +/- 18.5 pM and maximum binding was 94.2 +/- 12.5 fmol/mg of protein. Competition binding studies on dog heart membranes using 150 pM [125I] cyanopindolol indicated an order of potency (CGP 12177 > isoproterenol > BRL 37344) different from that observed in cardiovascular studies. Isoproterenol stimulated adenylate cyclase activity in heart membranes from normal dogs, whereas CGP 12177 and BRL 37344 were without any stimulating action. The positive chronotropic effects of isoproterenol, BRL 37344 and CGP 12177 were accompanied with a reduction in arterial blood pressure. In sinoaortic denervated animals, isoproterenol infusion provoked tachycardia and hypotension. BRL 37344 and CGP 12177 were without any significant effect on heart rate but induced a rapid and dramatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1992

Differential inhibition of the epidermal growth factor-, platelet-derived growth factor-, and protein kinase C-mediated signal transduction pathways by the staurosporine derivative CGP 41251.

The microbial alkaloid staurosporine is a potent but nonselective inhibitor of protein kinases. The derivative CGP 41251 has been shown to exert a high degree of selectivity for inhibition of protein kinase C activity. Both compounds are powerful inhibitors of proliferation of both normal and transformed cells in vitro and exert antitumor efficacy in vivo. In this work we have studied the mode of action of these compounds by analyzing their effects on early events in the induction of proliferation by different growth stimuli. Both drugs blocked the phorbol ester-induced expression of the c-fos proto-oncogene. The effect of CGP 41251 was reversible, since its removal led to a normal expression of c-fos mRNA in response to phorbol 12-myristate 13-acetate. Submicromolar concentrations of CGP 41251 and staurosporine directly inhibited both the platelet-derived growth factor (PDGF) receptor autophosphorylation and the c-fos mRNA expression induced by PDGF stimulation of intact BALB/c 3T3 cells. In contrast, ligand-induced epidermal growth factor receptor autokinase activity in A431 carcinoma cells and epidermal growth factor-dependent c-fos mRNA expression were relatively insensitive to inhibition by CGP 41251. Staurosporine suppressed signal generation by the epidermal growth factor receptor by reducing overall levels of the receptor. We conclude that CGP 41251 is a potent reversible inhibitor of protein kinase C and PDGF-mediated signal transduction. It inhibits the kinase activity of both protein kinase C and the PDGF receptor tyrosine kinase and the subsequent signaling cascade. The broad inhibition of kinases by staurosporine is also reflected at the cellular level and might contribute to the high toxicity of this compound, in comparison to CGP 41251.

3T3 Cells↗

PubMed1992

Effects of the novel NMDA receptor antagonist, CGP 39551, on field potentials and the induction and expression of LTP in the dentate gyrus in vivo.

The effects of the novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CGP 39551 [the carboxyethylester of CGP 37849; DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid], on extracellular field potentials and long-term potentiation (LTP) induced in the dentate gyrus by stimulation of the perforant path were studied in anesthetized rats. CGP 39551 attenuated the population spike (PS) and excitatory postsynaptic potential (EPSP) amplitude of dentate field potentials, reduced the NMDA receptor-mediated component of train-evoked burst potentials, and prevented the induction of LTP. The decrease in PS and EPSP amplitude produced by CGP 39551 was observed mainly in non-potentiated synaptic populations; potentiated field potentials were only minimally affected by drug treatment. These results are consistent with receptors may contribute in a tonic manner to the state of dentate granule cell excitability. Finally, the differential modulation of potentiated and non-potentiated synapses by CGP 39551 suggests that a change in some properties of postsynaptic AMPA receptors is involved in the expression of LTP.

2-Amino-5-phosphonovalerate↗

PubMed1992

Characterization of cell-surface beta-adrenergic ([3H]CGP-12177) binding in adult rat ventricular myocytes: lack of regulation by beta-agonists at physiological concentrations.

The major focus of this paper is the characterization and quantification of rat cardiomyocyte, cell-surface beta-adrenergic receptors labelled with the hydrophilic radioligand [3H]CGP-12177. The ventricular cardiomyocytes used in these experiments have previously been extensively studied in our laboratory and confirmed to be functionally compatible with similar cells in vivo. Specific binding of [3H]CGP was stereospecific, saturable and of high affinity. Binding of [3H]CGP was also readily reversible, demonstrated appropriate drug specificity and positively correlated with increasing cell concentrations. The potency of the beta 1-antagonist atenolol was almost 100 times higher than that of the beta 2-antagonist ICI-118.551 in binding to the [3H]CGP binding site. This preparation appears ideal for the investigation of beta-adrenergic receptor regulation in heart cells. Indeed, our initial experiments show clearly that pharmacological concentrations of isoproterenol, and norepinephrine, can reduce (down-regulate) the number of specific [3H]CGP binding sites. This result is in agreement with many other reports on similar experiments in a variety of cell types. However, physiologically relevant concentrations of these two agonists (1-100 nM) do not induce down-regulation of the beta-adrenergic receptors in short-term (2 h) incubations. Nevertheless, the high-affinity receptors that we have described mediate a contractile response to isoproterenol in the nanomolar concentration range (EC50 = 3.6 +/- 0.3 nM). This is approximately 300 times lower than the concentration needed to produce down-regulation. Thus, our data indicate that short-term down-regulation of cardiomyocyte beta-adrenergic receptors can only be observed with high, pharmacological concentrations of isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗

PubMed1992

Pharmacological characterization of a beta 3-receptor agonist (BRL 37,344) and a partial agonist (CGP 12,177A) in neonatal rat liver plasma membranes.

The pharmacological properties of BRL 37,344 (sodium-4-(2'-[2-hydroxy-2- (3-chloro-phenyl)ethylamino]-propyl)phenoxyacetatesesquihydrate), a beta 3-selective agonist, and CGP 12,177A) (-)-4-(3-t-butyl amino-2-hydroxypropoxy) benzimidazole-2-one], a non-selective beta-antagonist, recently characterized as a partial beta 3-agonist in rat adipose tissue, were studied in comparison with isoproterenol, a non-selective beta-agonist, in plasma membranes prepared from the livers of newborn rats. Competition binding curves obtained with [125I]iodocyanopindolol ([125I]CYP) as ligand and isoproterenol or BRL 37,344 as competitor were characterized by the presence of a high and a low affinity binding site; the high affinity binding site was no longer detectable when guanidylimidobisphosphate (GppNHp) was present in the incubation mixture. Competition curves with CGP 12,177A were monophasic and independent of GppNHp. In the presence of 10(-7) M of the beta 2-selective antagonist ICI 118,551 [erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylamino butan-2-ol], a concentration which blocks most of the beta 2-receptors, ligand binding was reduced to 32% of its maximum. Under these conditions, isoproterenol further displaced the ligand, and competition curves still displayed the high and the low affinity binding sites; BRL 37,344, however, caused no further displacement of ligand, except at the highest concentrations. This suggests that BRL 37,344 occupies only the ICI 118,551-sensitive binding sites, i.e. beta 2-receptors. Isoproterenol and BRL 37,344 both stimulated adenylate cyclase (EC 4.6.1.1) activity concentration dependently, although the stimulating effect of BRL 37,344 was about half of what was found for isoproterenol. Furthermore, BRL 37,344 inhibited concentration dependently the isoproterenol-induced stimulation of adenylate cyclase, and the inhibition was dependent on the concentration of isoproterenol. The stimulating effect of isoproterenol and BRL 37,344 on adenylate cyclase was blocked by ICI 118,551, whereas the beta 1-selective antagonist CGP 20,712A ((+/-)-(2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino)-3-[4-(1-methy l-4- trifluoromethyl-2-imidazolyl)-phenoxy]-2-propanolmethane sulphonate) was ineffective. CGP 12,177A failed to stimulate adenylate cyclase activity. From these results we suggest that BRL 37,344 acts as a beta 2-partial agonist in rat liver. The results obtained with CGP 12,177A are typical for a non-selective beta-antagonist. We therefore conclude that there is no pharmacological evidence for the presence of beta 3-receptors in livers from newborn rats.

Adenylyl Cyclase Inhibitors↗