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PubMed2000

The in vivo effects of beta-3-receptor agonist CGP-12177 on thyroxine deiodination in cold-exposed, sympathectomized rat brown fat.

OBJECTIVE: The effects of the beta-3-receptor agonist CGP-12177 on thyroxine (T4) deiodination in sympathectomized (SX) interscapular brown adipose tissue (BAT) were assessed in 300 g body weight (BW) Wistar rats. DESIGN: Seven days after SX, groups of rats were implanted s.c. with pellets containing 5mg CGP-12177 or 5mg norepinephrine (NE) and were immediately placed at 4 degrees C for 24h. Other SX groups were injected with CGP-12177 or NE 1mg/kg BW i. p. and placed in the cold for 4h. The latter group was injected, in addition, with prazosin 0.4 mg/100g BW i.p. or propranolol 0.5mg/100g BW i.p. 15 min before and 2h after the administration of CGP-12177 or NE. METHODS: Two hours after the last injection of prazosin or propranolol, animals were killed and BAT was removed, homogenized and centrifuged at 500 g for 10 min at 4 degrees C. The infranatants were incubated during 60 min in the presence of dithiothreitol and 1 microCi [(125)I]T4. Aliquots were chromatographed on paper for the measurement of [(125)I]T4 and its deiodinated subproducts. RESULTS: CGP-12177 restored normal T4 deiodination in SX BAT from both groups, but NE was slightly more effective. Propranolol, although not prazosin, blocked the CGP-12177 effects. Contrariwise, the NE-induced rise in deiodination was blocked by prazosin and to a lesser extent by propranolol. CONCLUSIONS: The results indicate that CGP-12177 stimulated the in vivo activation of 5'-deiodinase type II activity predominantly via beta-3-receptor, without participation of alpha-1-receptors.

Adipose Tissue, Brown↗

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↗

PubMed1985

Preferential renal vasodilator effects of CGP 22979A in conscious spontaneously hypertensive rats.

CGP 18137A (2-hydrazino-5-n-butyl-pyridine) and its prodrug CGP 22979A [N-acetyl-L-glutamic acid-N-[N2-(5-n-butyl-2-pyridyl)hydrazide]] were evaluated for their blood pressure-lowering potency and regional hemodynamic actions in conscious spontaneously hypertensive rats. The effects were compared to those of hydralazine. Animals were instrumented with miniaturized pulsed Doppler flowprobes to allow continuous simultaneous measurement of renal, mesenteric and hindquarter blood flow. From changes in mean arterial pressure and the respective flows, changes in renal, mesenteric and hindquarter resistance were calculated. After i.v. administration, hydralazine and CGP 18137A were equally potent with regard to their blood pressure-lowering effect in a dose range of 0.1 to 1 mg/kg. Hydralazine was more effective than CGP 18137A in lowering renal and hindquarter resistance. Neither of the two drugs, however, caused preferential dilation in any of the three beds studied. CGP 22979A in doses of 1 to 30 mg/kg caused a much smaller acute blood pressure-lowering response. However, already at low doses (1-10 mg/kg) it caused a significant reduction of renal resistance, without affecting either hindquarter or mesenteric resistance. At the highest dose (30 mg/kg), selectivity was no longer retained, which is probably due to excessive leakage of the active vasodilator into the peripheral circulation. These findings suggest that CGP 22979A is a renal-selective prodrug for CGP 18137A and thereby is capable of preferentially dilating the renal vasculature in conscious unrestrained spontaneously hypertensive rats.

Animals↗

PubMed1994

Weak allergenicity of recombinant hirudin CGP 39393 (REVASC) in immunocompetent volunteers. The European Hirudin in Thrombosis Group (HIT Group).

BACKGROUND: As a result of their polypeptidic nature, hirudins could theoretically elicit an immunologic response in humans. METHODS: The present open survey evaluates the allergenic potential of recombinant hirudin CGP 39393 (REVASC) after repeated intravenous or subcutaneous exposures in immunocompetent volunteers with no known previous exposure to hirudins. Clinical signs and symptoms of allergic manifestations and surrogate markers of allergy (i.e. response to skin tests) were collected before and after each administration of CGP 39393. Hirudin-specific immunoglobulin (Ig)G or IgE antibodies were measured. RESULTS: Two hundred and sixty-three healthy volunteers were eligible, of whom 12.2% had a history of allergy and 18.3% had a high level of total IgE. No signs or symptoms of allergy directly attributable to CGP 39393 were reported, either during or immediately after a first challenge. Irritative skin reactions, to either the prick or the intradermal skin test, were observed in eight volunteers 28-56 days after the challenge. Three out of 200 volunteers exposed to a second course of CGP 39393 showed signs and symptoms of an allergic reaction. In all but one subject with a pruritic erythema it was possible to rule out a causative role for CGP 39393 (0.50%, 95% confidence limits [CL] 0.01-2.75). Three other volunteers displayed a suspect or a positive immediate-type skin reaction to the follow-up intradermal skin test without any signs or symptoms of allergy. Another asymptomatic volunteer (0.80%, 95% CL: 0.02-4.41) developed a low [i.e. 1+ on the radio-allergosorbent test (RAST) scale] but measurable titre of hirudin-specific IgE antibodies after the second exposure to CGP 39393. A third exposure in five volunteers was clinically uneventful. A positive reaction to the prick test and to the intradermal skin test was observed in one individual. CONCLUSIONS: Recombinant hirudin CGP 39393 appears to be a weak allergen. Repeated exposures are safe in fully immunocompetent subjects, including those with a history of previous allergies and high levels of total IgE. Type I allergic reactions are rare (i.e. less than 1%) after a second exposure and are limited to the skin. Routine skin tests are not needed to identify patients at risk of developing type I allergic reactions. Hirudin-specific IgE antibodies are rarely seen and then at very low titres.

Adult↗

PubMedDate not supplied

Analysis of the antimetastatic effects of synthetic muramyl tripeptide (CGP 19835A) encapsulated in liposomes in combination with other immunomodulatory agents and chemotherapeutic drugs.

The synthetic molecule muramyl tripeptide (CGP 19835A) encapsulated in liposomes is effective in increasing the survival of mice with spontaneous experimental lung metastases induced by the RENCA renal adenocarcinoma and B16 melanoma tumor models. The present study was aimed at extending the effects of CGP 19835A to another highly metastatic carcinoma model and at evaluating the efficacy of combination therapy with standard cytotoxic agents and other immunomodulators. C57BL/6 mice received whole tumor implants of PancO2, a spontaneously metastasizing pancreatic adenocarcinoma, subcutaneously in the hind leg. Therapeutic effects were measured by increased survival which is a direct function of the growth of spontaneous lung metastases in this system. No therapeutic efficacy was observed with CGP 19835A alone or in combination with any of a series of cytotoxic or biological agents, including cis-platinurn (cis-Pt), mitomycin C (MMC), adriamycin (ADR), cyclophosphamide (CP), interferon gamma (IFN gamma), and interleukin 2 (IL-2). In accord with previous studies, when the B16-F10 melanoma was used as an experimental metastatic tumor model, CGP 19835A, alone and in combination with CP, significantly reduced the number of pulmonary metastases. Cis-Pt, however, partially negated the effects of CGP 19835A when a combination of the two agents was used. The results indicate that CGP 19835A is an effective therapeutic agent in some models of spontaneous or experimental lung metastases, but not others, and that the effects of CGP 19835A are not enhanced by the accompanying cytotoxic drugs tested here.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1994

CGP 48664, a new S-adenosylmethionine decarboxylase inhibitor with broad spectrum antiproliferative and antitumor activity.

Inhibitors of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), derived from methylglyoxal-bis(guanylhydrazone) (MGBG), have been shown to have significant antitumor activity in several human solid tumor systems (U. Regenass et al., Cancer Res., 52:4712-4718, 1992). From an ongoing effort to synthesize derivatives with increased enzyme specificity and potency and improved antitumor efficacy, we have now identified CGP 48664, a 4-amidinoindan-1-one 2'-amidinohydrazone (J. Stanek et al., J. Med. Chem., 36:2168-2171, 1993). The compound displays potent inhibition of SAMDC (50% inhibitory concentration, 5 nM), modest inhibition of diamine oxidase (50% inhibitory concentration, 4 microM), and no detectable inhibition of ornithine decarboxylase. CGP 48664 inhibits the growth of a panel of human and mouse tumor cell lines, including one which expresses the multidrug resistance phenotype, with 50% inhibitory concentrations ranging between 0.3 and 3 microM. CGP 48664 does not seem to utilize the polyamine transport carrier system since it competes poorly with spermidine for uptake into L1210 cells (Ki 161 microM) and inhibits the growth of polyamine transport-deficient Chinese hamster ovary cells. Relative to MGBG or previously described MGBG analogues, CGP 48664 accumulates to much lower intracellular concentrations. Treatment of the L1210 cell for 48 h with 3 microM CGP 48664 decreases SAMDC activity to < 10% of control and initiates a compensatory 3-fold rise in ornithine decarboxylase. Consistent with SAMDC inhibition, putrescine pools increase 10-fold, whereas spermidine and spermine pools fall to < 10% of control. In contrast to MGBG, CGP 48664 displays attenuated antimitochondrial activity as indicated by a lack of effect on pyruvate oxidation and mitochondrial DNA levels under treatment conditions which inhibit cell proliferation. Specificity of drug action was indicated further by prevention of L1210 cell growth inhibition by exogenous spermidine or spermine. More convincingly, Chinese hamster ovary cells made approximately 1000-fold resistant by chronic exposure to the analogue were found to selectively overexpress SAMDC mRNA due to gene amplification. The new SAMDC inhibitor showed potent antitumor activity against syngeneic tumors (B16 melanoma and Lewis lung carcinoma) and nude mouse human tumor xenografts (T-24 bladder carcinoma, SK MEL-24 melanoma, and MALME-3M melanoma). On the basis of its novel structure, its apparent specificity of action, and its potent antitumor activity, CGP 48664 is the candidate drug for further preclinical development.

Adenosylmethionine Decarboxylase↗

PubMed1996

Positive inotropic effects of the calcium sensitizer CGP 48506 in guinea pig myocardium.

In isolated papillary muscles from reserpinized guinea pigs, CGP 48506 increased force of contraction in a concentration-dependent and reversible manner, starting at 10 mumol/l and reaching 364.14 +/- 46.10% of predrug values at 100 mumol/l. The positive inotropic effect of CGP 48506 was not sensitive to 10 mumol/l carbachol. The positive inotropic effect of CGP 48506 was accompanied by increases in time to peak tension and in time of relaxation amounting to 223.37 +/- 6.87% and 247.10 +/- 9.34% of control, respectively, at 100 mumol/l (n = 10). CGP 48506 sensitized trabeculae from guinea pig hearts to calcium with an EC50 value of 22 mumol/l. However, CGP 48506 (up to 300 mumol/l) did not affect the activity of cardiac PDE isoenzymes I to IV. Likewise, CGP 48506 (up to 100 mumol/l) did not increase phosphorylation of select cardiac regulatory proteins or cyclic AMP content in guinea pig ventricular cardiomyocytes and did not affect cardiac phosphorylase phosphatase activity. CGP 48506 is the first pharmacological agent with noteworthy calcium-sensitizing properties that has been found to be devoid of inhibitory activity on cardiac PDE.

1-Methyl-3-isobutylxanthine↗

PubMed1996

Retinoic acid-induced RB (retinoblastoma) hypophosphorylation enhanced by CGP 52411 (4,5-dianilinophthalimide), an EGF family tyrosine kinase receptor inhibitor.

Retinoic acid is a known morphogen which can regulate cell proliferation and differentiation and also induces the hypophosphorylation of the RB (retinoblastoma tumor suppressor gene) protein, a known cell cycle regulatory protein. The mechanism by which these processes occur is unclear. We find that these processes can be regulated by CGP 52411, 4,5-dianilinophthalimide, an inhibitor of tyrosine protein kinases of the EGF receptor subfamily. Retinoic acid causes the largely phosphorylated RB protein expressed in proliferating HL-60 human promyelocytic leukemia cells to shift to the unphosphorylated form, as well as causing the cells to G0 arrest and differentiate. Addition of CGP 52411 accelerated the redistribution of the RB protein expressed in HL-60 cells to the unphosphorylated form, enhancing the effects of the retinoic acid. By itself CGP 52411 had no apparent effect on the RB protein expressed in HL-60 cells. CGP 52411 also accelerated the retinoic acid-induced accumulation of cells in G1/0 and the phenotypic conversion of cells to the mature myeloid phenotype, suggesting that its target is common to the regulation of both RB phosphorylation and cell proliferation and differentiation. CGP 52411 had a similar effect on the RB phosphorylation shift induced by 1,25-dihydroxy vitamin D3, a ligand for a receptor in the same steroid thyroid hormone superfamily as retinoic acid. Increasing the concentration of CGP 52411 enhanced the acceleration of RB hypophosphorylation in the case of both retinoic acid and 1,25-dihydroxy vitamin D3. The data are consistent with the negative regulation of retinoic acid induced RB protein dephosphorylation coupled to cell cycle arrest and differentiation by a receptor tyrosine kinase sensitive to CGP 52411.

Calcitriol↗

PubMedDate not supplied

Locomotor activity and motor disturbances induced by the competitive NMDA receptor antagonist CGP 37849.

The study compares the effects of the competitive NMDA receptor antagonist, CGP 37849, on the locomotor activity and motor disturbances after local, unilateral microinjection into nucleus accumbens and caudateputamen or peripheral ip administration. Independently on the route of administration, the compound induced dose-dependent increase in the locomotor activity as well as the symptoms of motor disturbances. In all cases the symptoms of motor disturbances appeared earlier and lasted longer than increase in locomotor activity induced by the same dose of the drug. The long-lasting observation indicated, that CGP 37849 administered in a dose of 20 mg/kg ip increased the locomotor activity of the rats for about 2 h while motor disturbances persisted for about 6 h. Administration of the lowest dose of CGP 37849, i.e. 0.05 microgram into the nucleus accumbens, or 10 mg/kg ip-while without any effect on the locomotor activity-induced the symptoms of motor disturbances. Pretreatment with SKF-525-A (proadifen, an agent inhibiting the metabolism of the drugs), fully antagonized the locomotor hyperactivity induced by CGP 37849 given in a dose of 20 mg/kg, and-in the same time-diminished the degree of motor disturbance symptoms. On the other hand, in the case of the dose of 10 mg/kg of CGP 37849, SKF-525-A did not affect the locomotor activity, but enhanced the motor disturbance symptoms induced by this dose of CGP 37849. In conclusion, the obtained results indicate that CGP 37849 administered peripherally or locally to the brain regions cited above induces motor disturbances at doses lower (or at least similar) than these which stimulate the locomotor activity.

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Treatment of human glioblastoma cells with the staurosporine derivative CGP 41251 inhibits CDC2 and CDK2 kinase activity and increases radiation sensitivity.

CGP, 41251, a staurosporine derivative, is a potent inhibitor of protein kinase C (PKC). In recent studies we found that this compound causes growth inhibition and induces apoptosis in human glioblastoma cell lines and also inhibits the growth of xenografts of a human astrocytoma. In this study we investigate its effects on cell cycle control. Treatment of glioblastoma or gliosarcoma cells with CGP 41251 lead to a time and dose dependent increase of the percentage of cells in the G2-M phase of the cell cycle. This correlated with a decrease of CDC2- and CDK2-associated histone H1 kinase activities as well as a decrease in the cellular level of the CDC2 protein. The decrease of CDC2- associated histone H1 kinase activity was detected within 5 hours, and there was complete inhibition after 24 hours. Assays of mixtures of cell extracts obtained from cultures treated with CGP 41251, the inactive analog CGP 42700, or untreated cultures indicated that this decrease was due to a decrease in the CDC2 kinase itself rather than the accumulation of an inhibitor of this kinase. In vitro assays in which CGP 41251 was added directly to the in vitro assay system revealed marked inhibition of both CDC2- and CDK2-associated kinase activity at about 1 microM. Thus CGP 41251 inhibits CDC2- and CDK2-associated kinase activities both in vivo and in vitro. Its biologic effects may, therefore, not be due simply to inhibition of PKC. Since cells in the G2-M phase of the cell cycle are relatively more sensitive to killing by gamma- radiation than cells in other phases of the cell cycle, we carried out radiosensitization studies. We found that CGP 41251 was a radiation sensitizer in two glioblastoma cell lines. Therefore, this compound may be useful in the treatment of glioblastomas, possibly in combination with radiation therapy.

Antineoplastic Agents↗

PubMed1995

Biochemical and growth-modulatory effects of the new S-adenosylmethionine decarboxylase inhibitor CGP 48664 in malignant and immortalized normal human breast epithelial cells in culture.

CGP 48664 [4-aminoindanon-1-(2'-amidino)hydrazone dihydrochloride monohydrate] is a newly introduced inhibitor of S-adenosylmethionine decarboxylase (SAMDC) with increased selectivity of action and reduced toxicity. We analyzed the biochemical and antiproliferative effects of this compound in a panel of hormone-dependent (3 clones of MCF-7, T47D) and -independent (MDA-MB-231, BT-20) human breast cancer cell lines in culture. For comparison, we also tested its effects in the spontaneously immortalized human breast epithelial cell line MCF-10A. All cell lines were highly sensitive to the growth-inhibitor effect of CGP 48664 with an IC50 between 0.1 and 0.5 microM. A dose-dependent bell-shaped increase in SAMDC was observed in normal and malignant breast cells resulting from enzyme stabilization by the inhibitor as supported by Western blot analysis. While ornithine decarboxylase (ODC) activity consistently increased, the effect of CGP 48664 on spermidine/spermine N'acetyltransferase (SSAT) was variable in the breast cancer cell lines. In contrast, the inhibitor consistently reduced SSAT activity level in the MCF-10A cell line and its derivative partially transformed by a mutated ras oncogene. As expected cellular putrescine levels were markedly increased by CGP 48664 administration, whereas spermidine and spermine contents were reduced. However, the degree of reduction was usually only moderate. Furthermore, exogenous polyamine administration was relatively ineffective in rescuing the antiproliferative effect of CGP 48664 in MCF-7 cells, while exerting a more complete rescue in the MDA-MB-231 cell line. We conclude that CGP 48664 exerts a potent growth-inhibitory effect on mammary cells in culture. However, its action may not always be entirely mediated through the polyamine pathway.

Acetyltransferases↗

PubMed2001

Characterization of [3H]CGP 12177 binding to beta-adrenergic receptors in intact eel hepatocytes.

The aim of this study was to characterize [3H]CGP 12177 (CGP) binding to beta-adrenergic receptors in isolated hepatocytes of the European eel (Anguilla anguilla), in which the involvement of cAMP in epinephrine-induced glucose release has been previously observed. Specific binding of CGP was saturable, reversible, and linear as a function of cell number. Analysis of binding data suggested a single class of binding sites, with a Kd of 1.31 nM and a number of approximately 7000 beta-adrenergic receptors per cell. The potency order of specific inhibition of [3H]CGP binding was CGP > propranolol > or = alprenolol >> butoxamine > or = atenolol, while phentolamine and prazosin failed to significantly displace the tracer at concentrations up to 100 microM. The binding kinetics of CGP were closely related to its biological effect. In fact, the drug dose-dependently counteracted the enhancement of intracellular cAMP levels induced by epinephrine in isolated hepatocytes with a Kd of 1.06 nM. Moreover, it antagonized the hormone-induced stimulation of adenylyl cyclase activity in hepatic membranes as well as of glucose release from cells. These data clearly show that beta-adrenergic receptors are coupled to the adenylyl cyclase/cAMP transduction pathway in eel liver.

Adenylyl Cyclases↗

PubMed1987

The role of a low beta 1-adrenoceptor selectivity of [3H]CGP-12177 for resolving subtype-selectivity of competitive ligands.

On the basis of saturation binding studies on rat cardiac microsomes, which contained a mixed population of beta-adrenoceptor subtypes, [3H]CGP-12177 is presumed to be a non-selective beta-adrenergic radioligand. However, saturation binding studies carried out in the presence of subtype-saturating concentrations of the beta 2-selective antagonist ICI 118,551 and the beta 1-selective antagonist ICI 89,406, respectively, revealed a KD for beta 1-adrenoceptors of 0.33 +/- 0.02 nmol/l and a KD for beta 2-adrenoceptors of 0.90 +/- 0.14 nmol/l. Competition experiments with the highly selective antagonists revealed greatly different competition binding curves in the presence of either [3H]CGP-12177 or (-)[125I]iodocyanopindolol (ICYP), a beta-adrenergic radioligand considered to be as non-selective as [3H]CGP-12177. The following results are further suggestive for a selectivity of [3H]CGP-12177 for beta 1-adrenoceptors: (1) Using non-linear regression analysis, a significantly lower selectivity (expressed as the ratio of the IC50 for beta 2-adrenoceptors to the IC50 for beta 1-adrenoceptors) as well as a larger proportion of beta 1-adrenoceptors were calculated by competition of the beta 1-selective antagonist ICI 89,406 with [3H]CGP-12177 binding than by competition of ICI 89,406 with ICYP binding; (2) reducing the [3H]CGP-12177 concentration from 2 to 0.4 nmol/l, competition experiments with ICI 89,406 led to an increase in the estimated selectivity of the competitor and in the estimated proportion of beta 1-adrenoceptors; (3) reverse findings were obtained with ICI 118,551, a beta 2-selective antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1983

Effects of CGP 11305 A, a new reversible and selective inhibitor of MAO A, on biogenic amine levels and metabolism in the rat brain.

CGP 11305 A [4-(5-methoxy-7-bromo-benzofuranyl-2)piperidine HCl), a reversible, selective inhibitor of MAO A, increased the levels of rat brain noradrenaline, dopamine, and serotonin dose-dependently and to approximately the same extent. Concomitantly, it lowered the levels of their metabolites, MHPG-SO4, HVA, DOPAC, and 5-HIAA. When compared with the irreversible MAO A inhibitor clorgyline, the effects of CGP 11305 A were of much shorter duration. Moreover, the increases of noradrenaline and serotonin and the decreases of their metabolites MHPG-SO4 and 5-HIAA were smaller after CGP 11305 A than after clorgyline in equieffective doses for MAO A inhibition. CGP 11305 A decreased the synthesis of catecholamines and serotonin less markedly than clorgyline. This is probably due to the reversibility of the interaction of the compound with MAO A. In contrast to CGP 11305 A, clorgyline increased the level of dopamine less than those of noradrenaline and serotonin. This is explained by assuming that dopamine synthesis is particularly sensitive to end product inhibition. CGP 11305 A also exhibited some inhibitory properties on the uptake of serotonin and, to a lesser degree, of noradrenaline in vitro and in vivo. Compared with MAO inhibition, however, uptake inhibition required 30-100 times higher doses.

Animals↗

PubMed1983

Urinary excretion of O-methylated catecholamines, tyramine and phenyl-ethylamine by volunteers treated with tranylcypromine and CGP 11305 A.

To assess the effect of the new, selective, reversible MAO A inhibitor, CGP 11305 A (4-(5-methoxy-7-bromo-benzofuranyl-2-)piperidine HCl), on MAO A and B activity in man, the daily excretion of total normetanephrine (NMN), metanephrine (MN), 3-methoxytyramine (3-MT) and beta-phenylethylamine (PEA) was measured in the urine of healthy volunteers treated with weekly increasing doses from 40 to 150 mg/d. A similar study was carried out with tranylcypromine in weekly increasing doses from 10 to 25 mg/d. Both compounds increased the excretion of NMN; with CGP 11305 A, a plateau was obtained at 50 mg/d, and tranylcypromine 20 mg was more effective than 10 mg, and was also more active than the highest dose of CGP 11305 A. Increases in MN and 3-MT produced by the latter compound were comparable to that in NMN, whereas tranylcypromine had a biphasic effect on MN excretion, and caused only a small increase in 3-MT excretion. CGP 11305 A up to 150 mg/d did not alter total tyramine excretion, whereas tranylcypromine at 20 mg caused a definite increase. Tranylcypromine led to 4-6 fold increases in PEA output at 20 and 25 mg/d, but not at 10 mg. No such effect could be demonstrated for CGP 11305 A up to 150 mg/d. These results suggest that in man MAO A was inhibited by CGP 11305 A in daily dose of 40 mg or more, whereas it did not affect MAO B at up to 150 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1983

Reversibility of the interaction of CGP 11305 A with MAO A in vivo.

The aim of this study was to resolve the apparent discrepancy between the short duration of action of the MAO inhibitory effect of CGP 11305 A in vivo and its irreversible interaction with the enzyme in vitro. When rats were treated with CGP 11305 A 2 h prior to clorgyline administration and MAO activity was determined 46 h thereafter, MAO A in brains and livers was protected from inhibition by clorgyline provided the dose relation was adequate. However, if clorgyline doses were equal to or higher than those of CGP 11305 A, there was only partial or no protection despite the fact that the doses of CGP 11305 A blocked MAO A nearly completely at the moment of clorgyline administration. Using a different approach, it was found that dopamine and serotonin released from their stores in rat striatum by tetrabenazine could displace CGP 11305 A from the MAO A active site in vivo, in contrast to clorgyline. These results suggest that the interaction of CGP 11305 A with MAO in vivo is reversible and competitive.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Effects of the competitive NMDA receptor antagonist, CGP 37849, on anticonvulsant activity and adverse effects of valproate in amygdala-kindled rats.

The effects of combined treatment with low doses (1-5 mg/kg i.p.) of the competitive NMDA receptor antagonist, CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. CGP 37849, 5 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 80 mg/kg i.p. However, the increase in anticonvulsant activity was parallelled by a marked increase in motor impairment, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, at doses of 2.5-5 mg/kg, CGP 37849 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. In non-kindled rats, combined treatment with CGP 37849 and valproate induced significantly less marked adverse effects than in kindled rats. The data on combined treatment with CGP 37849 and valproate substantiate that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events. Since kindling is thought to be a predictive model of complex partial seizures, these results suggest that competitive NMDA receptor antagonists such as CGP 37849 may be of limited usefulness against this seizure type in humans.

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Autoradiographic localization of a non-reducible somatostatin analog (125I-CGP 23996) binding sites in the rat brain: comparison with membrane binding.

The regional distribution of somatostatin binding sites in the rat brain was determined by quantitative autoradiography, using 125I-CGP 23996, a non-reducible somatostatin analog. In preliminary experiments, kinetic properties of 125I-CGP 23996 binding to rat brain membranes and slide mounted frozen brain sections were compared and found similar. In addition, distribution of 125I-CGP 23996 and 125I-N-Tyr-SRIF14 binding sites on membrane prepared from 10 different rat brain structures were closely correlated (r = 0.91, 2 p less than 0.01), indicating that the non-reducible analog recognizes the same binding site as the Tyr-extended native peptide. Highest levels of 125I-CGP 23996 binding sites were found in anterior temporal, frontal and cingular cortex as well as hippocampus. Moderate levels were found in the remaining part of the limbic system including amygdala, olfactory tubercles and bed nucleus of the stria terminalis. In the brain stem, nuclei involved in the auditory system such as the ventral cochlear nucleus and the superior olive nucleus, contained high levels of 125I-CGP 23996 binding sites. The distribution of 125I-CGP 23996 binding sites roughly correlated with that of the endogenous peptide in most structures, except in the mediobasal hypothalamus.

Amygdala↗