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Biomedical subjects

G Petrone

Publications and source records attributed to G Petrone.

At least 37 records · Page 2Linked to original sources
PubMed1994

Selective kappa-opioid agonists: synthesis and structure-activity relationships of piperidines incorporating on oxo-containing acyl group.

This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using kappa-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective kappa-agonists, has a reduced propensity to cause a number of kappa-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 mumol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.

Analgesia↗
PubMed1994

Antinociceptive effects of non-steroidal anti-inflammatory drugs in a rat model of unilateral hindpaw inflammation.

The antinociceptive activity of intramuscular 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone, was examined in a rat model of unilateral hindpaw inflammation/hyperalgesia and compared with that of three other non-steroidal anti-inflammatory drugs (NSAIDs)--diclofenac, naproxen and piroxicam. Over a dose range of 10-100 mg/kg i.m., 6-MNA produced a dose-dependent increase in the withdrawal threshold to a noxious mechanical stimulus applied to the inflamed paw; however, a higher dose (300 mg/kg) produced no further increase in antinociceptive activity. Peak effects occurred 30 min after intramuscular injection. Diclofenac, naproxen and piroxicam produced antinociceptive effects that were qualitatively similar to those of 6-MNA. There was an indication of quantitative differences between the four NSAIDs in terms of potency and efficacy although this was not statistically significant. The rapid onset of effect and the lack of correlation between the relative antinociceptive effects of the four NSAIDs and the anti-inflammatory activities (assayed as inhibition of carrageenan-induced rat paw oedema) suggest that their pain relieving properties may not be entirely the result of their anti-inflammatory effects. These experimental data support the therapeutic value of 6-MNA as an analgesic in conditions of inflammatory pain.

Analgesics↗
PubMed1994

Intramedullary haemorrhage due to AVM located within the medulla oblongata in a three year old child. Case report.

Intramedullary arteriovenous malformations are rare in childhood. Yasargil reports only two cases in children under ten years of age out of a total of forty-one cases of AVM operated on between 1967 and 1983 in which microsurgical techniques were used. The early symptoms of these lesions are those due to intramedullary or subarachnoid haemorrhage with neurological deficit, pain and/or weakness or numbness of one or more limbs. We report the case of an intramedullary haematoma due to arteriovenous malformation within the medulla oblongata in a three year old child admitted for cervical pain and right arm hypostenia. The CT scan and MRI showed an intramedullary expansive lesion with associated internal haematoma between C1-C7 level. Because of the rapid clinical deterioration upon the onset of right hemiparesis we procedeed to empty the intramedullary haematoma and to remove the intrabulbar AVM. A swift improvement of neurological deficit was observed along with a total regression of the symptomatology in a month's time. The excellent results reported in this case, very likely the only case in the literature occurring in a very small child at this spinal cord level, are mostly due to the early surgical treatment and to the exact information that MRI provided.

Child, Preschool↗
PubMed1994

Effect of detergents on the chicken liver F1-ATPase: functional and structural aspects.

The hydrolytic activity of the chicken liver F1-ATPase is strongly inhibited by detergents. The inhibition is concentration dependent and the highest value is obtained at the critical micelle concentration. Cationic and anionic detergents are good inhibitor of the enzyme, however the inhibition is correlated rather with the micelle size than the charge of the detergent as demonstrated by the inhibition observed with the non-ionic beta-D-alkyl glucosides. The effect of detergents upon subunits interactions was studied by trypsin limited proteolysis. Incubation with cholate results in the proteolytic cleavage of the alpha and gamma subunits whereas in the presence of DTAB also the beta subunit is digested. The small subunits delta and epsilon instead are not accessible when the enzyme is treated with both detergents. The results may suggest that hydrophobic areas of defined size located at the interface among alpha, beta and gamma subunit are crucial for the catalytic activity of the enzyme.

Animals↗
PubMed1994

Contribution of alpha-2 adrenoceptors to kappa opioid agonist-induced water diuresis in the rat.

Clearance studies in rats using kappa opioid agonists have demonstrated that agonists that can cross the blood-brain barrier are more potent water diuretics than agonists which have limited access to the brain. The mechanism of kappa agonist-induced water diuresis is unclear but may involve inhibition of vasopressin secretion and/or an adrenomedullary factor. In the present study the effect of an alpha-2 adrenoceptor antagonist (yohimbine, 10 micrograms/kg.min i.v.) on kappa agonist-induced water diuresis was evaluated in conscious chronically instrumented rats. BRL 53117 (1-[(3,4-dichlorophenyl)acetyl]-2-[(3-hydroxy-1-pyrrolidinyl) methyl]4,4-dimethyl piperidine), a kappa agonist that can cross the blood-brain barrier, caused a dose-dependent (1-100 micrograms/kg) water diuresis which was attenuated by yohimbine. The effective dose to cause a free water clearnace of zero for BRL 53117 was 13 +/- 5 micrograms/kg in vehicle-treated rats and 37 +/- 12 micrograms/kg in yohimbine-treated rats. BRL 52974 (5-[(3,4-dichlorophenyl)acetyl]4-(1-pyrrolidinylmethyl)-4,5,6,7-te trahydro- 1H-imidazo[4,5-c]pyridine), a compound with limited ability to cross the blood-brain barrier, also caused a dose-dependent water diuresis, albeit at higher doses (30-3000 micrograms/kg), and thus a higher effective dose to cause a free water clearance of zero (129 +/- 61 micrograms/kg); however, the effect was abolished by yohimbine. The data suggest that kappa agonists cause a water diuresis by both a central mechanism involving inhibition of vasopressin secretion and a peripheral mechanism involving stimulation of renal alpha-2 receptors.

Animals↗
PubMed1993

Opiate receptors within the blood-brain barrier mediate kappa agonist-induced water diuresis.

Data suggest that kappa opioid agonist-induced water diuresis involves inhibition of vasopressin (AVP) secretion; however, it is not clear whether this action involves kappa receptors in the neurohypophysis or receptors behind the blood-brain barrier (BBB). We have investigated the site of action using three selective kappa agonists, BRL 52656 (S(-)-2-(1-pyrrolidinylmethyl)-1-(4-trifluoromethylphenyl) acetyl piperidine hydrochloride), BRL 53114 ((-)-1-(4-trifluoromethylphenyl) acetyl-2-(1-pyrrolidinymethyl)3,3- dimethyl piperidine hydrochloride) and BRL 52974 (4-(1-pyrrolidinylmethyl)5-(3,4-dichlorophenyl)acetyl-4,5,6,7-t etrahydroimidazo [4,5-c] pyridine), with varying abilities to cross the BBB. Chemical and functional assays indicate that BRL 52974 has limited ability to cross the BBB, whereas BRL 53114 and BRL 52656 can freely penetrate. BRL 52974 was significantly less potent than BRL 52656 and BRL 53114 in causing a water diuresis in conscious rats. The ED10S (i.v. doses to cause a positive free water clearance of 10 microliters/min.100 g) for BRL 52974, BRL 52656 and BRL 53114 were 181, 9 and 3.4 mg/kg, respectively. Furthermore, in dogs BRL 52656 and BRL 53114 but not BRL 52974 (30 micrograms/kg i.v.) were able to cause a significant water diuresis. The data demonstrate that opiate receptors behind the BBB are primarily involved in kappa agonist-induced water diuresis and possibly inhibition of AVP secretion.

Animals↗
PubMed1992

Substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines: a novel class of very potent antinociceptive agents with varying degrees of selectivity for kappa and mu opioid receptors.

This study describes the synthesis of a series of novel substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines, and discusses their structure-activity relationships (SARs) using binding affinity for opioid receptors and antinociceptive potency as the indices of biological activity. The introduction of a hydroxy substituent in position 5 of the isoquinoline nucleus generated a compound, 40, which is 2 times more potent than the previously disclosed unsubstituted analogue 39 in mouse models of antinociception. A QSAR analysis of the 5-substitution clearly demonstrates that antinociceptive activity is inversely associated with the lipophilicity of the substituents. The substituted compounds described herein are less selective for the kappa opioid receptors than the unsubstituted isoquinoline 39. For example, the 5-hydroxy-substituted compound 59 shows high affinity for kappa opioid receptors (Ki kappa = 0.09 nM) and a Ki mu/Ki kappa ratio of only 5. However, a multiple linear regression analysis demonstrates a lack of correlation between antinociceptive activity and affinity for the mu opioid receptor. On the other hand, the correlation between binding affinity to kappa opioid receptor and antinociceptive activity was statistically significant.

Analgesics↗
PubMed1992

Enantiospecificity of kappa receptors: comparison of racemic compounds and active enantiomers in two novel series of kappa agonist analgesics.

Two novel series, Ia,b and IIa,b, of kappa opioid antinociceptive agents have recently been described. 2a,b,3a,b,c The biological activities of 16 racemic compounds and their corresponding (-) enantiomers are now compared in a battery of tests. Enantiomers of unsubstituted piperidines Ia were synthesized starting from S(-) pipecolic acid, whereas the enantiomerically pure substituted piperidines (Ib), tetrahydroisoquinolines (IIa), and thienopiperidines (IIb) were, in general, obtained after diastereomeric crystallization of the corresponding tartrate salts. The absolute stereochemistry of one representative enantiomer from series IIa was determined to be (1S) by X-ray crystallographic analysis. Antinociceptive activity in the mouse abdominal constriction and tail-flick tests following subcutaneous administration, and binding affinity for kappa and mu receptors, were found to reside predominantly in the (-) enantiomers. Consequently, racemic compounds showed approximately half potency of the corresponding enantiomers. This potency difference was less clear after oral administration presumably due to small differences in bioavailability of the two corresponding enantiomers. For compounds with some affinity also for mu receptors (Ki less than 1,000 nM), the kappa/mu selectivity was maintained within each enantiomeric pair, in contrast to results found for other kappa agonists.

Analgesics↗
PubMed1992

Purification and properties of the F1-ATPase from liver mitochondria of Gallus gallus.

1. This paper is the first detailed report of the purification of a mitochondrial ATPase from an avian species. 2. The Gallus gallus liver mitochondrial F1-ATPase was purified by chloroform extraction and ion-exchange chromatography. 3. The enzyme shows the five alpha, beta, tau, delta, and epsilon subunits characteristic of mitochondrial F1-ATPases. 4. The Km for ATP is 1 mM and for Mg 0.5 mM with a specific activity of 25.2 mu moles of ATP hydrolyzed x min-1 x mg-1. 5. Unlike mammals enzymes the chicken mitochondrial ATPase shows maximal activity with ITP as substrate, and is strongly inhibited by Cu.

Adenosine Triphosphate↗
PubMed1991

(1S)-1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: members of a novel class of very potent kappa opioid analgesics.

The synthesis and structure-activity relationship (SAR) of a novel class of kappa opioid analgesics, 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4- tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines+ ++, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60 degrees was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of kappa receptor selectivity was a feature of this novel class of antinociceptive agents (mu/kappa ratio from 44 to 950 according to the nature of the basic moiety). SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 microM/kg sc) and kappa ligands (Ki(kappa) ca. 0.20 nM) identified so far.

Analgesia↗
PubMed1988

Interaction of phenylisothiocyanates with the mitochondrial phosphate carrier. I. Covalent modification and inhibition of phosphate transport.

The effects of phenylisothiocyanate (PITC) and of the polar analogue p-sulfophenylisothiocyanate (p-sulfoPITC) on the phosphate carrier of bovine heart mitochondria have been investigated. Incubation of mitochondria with the two phenylisothiocyanates leads to inhibition of the phosphate carrier protein. The inhibition of phosphate transport by PITC is unaffected by the addition of dithioerythritol (DTE) or by variation of the pH. The inhibition by p-sulfoPITC is in part removed by DTE; the remaining inactivation of the phosphate carrier, which can be attributed to the reaction with NH2 groups, is temperature and pH-dependent. Inhibition of phosphate transport by both p-sulfoPITC and PITC depends on the time of incubation and the concentration of the inhibitor. Preincubation with mersalyl protects the carrier protein against the inactivation by p-sulfoPITC but not against PITC. Other SH reagents tested do not show any protective effect. It can thus be concluded that two types of lysine residues are essential for the activity of the phosphate carrier. Lysine(s) of the former type are located at the surface of the membrane and are topologically related to the functional SH groups of the protein. Lysine residue(s) of the latter type are buried in the hydrophobic phase of the membrane.

Animals↗
PubMed1988

Identification of iodination sites in cytochrome c by high-performance liquid chromatography and fast atom bombardment mass spectrometry.

Site-directed covalent modification of proteins is currently used to study the molecular structure of enzyme active sites. Radioactive labels together with protein sequencing by Edman degradation have been previously employed to identify the site of modification. One drawback of such a procedure is that most reagents are not commercially available in radioactive form. Moreover, the covalent bond formed upon reaction of the label with the protein may be labile under the conditions of Edman degradation. By combining reverse-phase high-performance liquid chromatography (RP-HPLC) and fast atom bombardment (FAB) mass spectrometry, we have been able to identify the modified sites of horse heart cytochrome c after reaction with iodine. By using this procedure it has been possible to ascertain that, among the four tyrosines contained in the sequence of horse heart cytochrome c, only tyrosine 74 is converted into the monoiodinated derivative. The data demonstrate also the absence of unwanted secondary reactions. The technique avoids the use of radioactive materials and prevents losses of the label since Edman degradation is not required to identify the modified peptides. These results indicate that FAB mass spectrometry along with RP-HPLC is potentially a powerful technique to study chemical modifications of proteins.

Amino Acids↗
PubMed1987

Mitochondrial ATP synthase complex: interaction of its F1 adenosinetriphosphatase moiety with the heavy atom iodine.

Studies were carried out to determine whether a simple electron-dense "heavy atom" like iodine could be introduced selectively into one or more of the subunits of the mitochondrial ATP synthase complex of rat liver. Surprisingly, very low amounts of iodine are incorporated into the isolated F1 moiety of this complex under conditions which result in a marked loss of catalytic activity. ATPase activity is inactivated in a concentration-dependent manner at pH 7.5 with half-maximal inactivation occurring at about 40 microM iodine. A maximum of only 10 atoms of iodine are incorporated per F1 molecule under conditions where inhibition of ATPase activity is linearly related to iodine incorporation. The molecular size of F1 after iodination is unchanged, indicating that inactivation is due to modification of essential amino acid residues rather than subunit dissociation. Treatment of F1, with 20-50 microM [125I]iodine followed sequentially by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography showed that the beta subunit is preferentially labeled. Significantly, about two atoms of iodine per beta subunit are incorporated. Some iodine amounting to less than 23% of the total radioactivity placed on the gels is recovered in the alpha and gamma subunits whereas no radioactivity is detected in the delta and epsilon subunits. Iodination of F1 appears to modify essential residues other than those involved in substrate or product binding per se. Thus, nucleotide binding to F1 is unaltered by iodine, and neither phosphate, MgADP, nor MgATP protects F1 against inhibition by this agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Proton translocation by a native and subunit III-depleted cytochrome c oxidase reconstituted into phospholipid vesicles. Use of fluorescein-phosphatidylethanolamine as an intravesicular pH indicator.

The existence of a proton pump associated with bovine cytochrome c oxidase (EC 1.9.3.1) has over the last few years been a matter of considerable dispute. In an attempt to resolve some of the problems with the measuring system we have synthesized fluorescein-phosphatidylethanolamine which when reconstituted with cytochrome c oxidase into phospholipid vesicles provided a reliable indicator of the intravesicular pH. It was observed that cytochrome c oxidase catalyzed the abstraction of almost 2 protons from the intravesicular medium/molecule of ferrocytochrome c oxidized. In parallel experiments whereby the extravesicular pH was measured with an electrode it was found that the enzyme appeared to be responsible for the appearance of almost 1.0 proton/molecule of ferrocytochrome c oxidized. Taken together these data unequivocally demonstrate that cytochrome c oxidase behaves as a proton pump. Furthermore, the other proton which was abstracted is believed to be used for the process of the reduction of oxygen. Similar experiments were performed with a cytochrome c oxidase preparation which was devoid of subunit III. Under these circumstances the enzyme appeared to be unable to translocate protons across the vesicular membrane but was competent to abstract protons from the intravesicular medium for the reduction of oxygen.

Animals↗
PubMed1984

The use of fluorescein-dipalmitoylphosphatidylethanolamine for measuring pH-changes in the internal compartment of phospholipid vesicles.

The synthesis and characterisation of fluorescein-phosphatidylethanolamine (FPE) is described. The effects of dielectric constant, ionic strength and ambient pH upon the optical absorbance properties of FPE are presented. It is shown that under appropriate conditions, FPE rapidly and quantitatively reports the pH of the aqueous bulk phases when incorporated into phospholipid vesicles. It is also shown that, when the external medium is highly buffered, FPE is capable of specificity reporting only the pH of the intravesicular compartment. The application of FPE for studies of intravesicular pH changes of reconstituted membranous protein systems is discussed.

Electric Conductivity↗
PubMed1984

The current-voltage relationships of liposomes and mitochondria.

Current-voltage relationships were determined for various membrane systems. We show that phospholipid and mitochondrial membranes exhibit linear relations between H+ flux and pH gradients. These membranes, however, exhibited non-linear relationships when the applied voltage was a membrane potential. The current-voltage relationship approximated to an exponential function. This relationship was found to be linearized when the membranes were treated with an electrogenic proton ionophore. The incorporation of cytochrome c oxidase (EC 1.9.3.1) was found to have no effect on the current-voltage characteristics of the phospholipid membranes. When a membrane potential of more than 140 mV was imposed across vesicular and mitochondrial membranes, they exhibited reversible di-electric breakdown. This phenomenon was correlated with the requirement of a permeant ion for the experimental demonstration of proton translocation by so-called 'proton pumps'.

Animals↗
PubMed1981

Actinomycotic granuloma of the Gasserian ganglion with primary site in a dental root. Case report.

An unusual case of cerebral actinomycosis of the Gasserian ganglion is reported. The location and the pathological diagnosis of granuloma are both extremely rare. The literature is briefly reviewed with special reference to similar reports. The manner of spread and the course of the disease are described. The present case tends to confirm the opinion that primary cerebral actinomycosis is extremely rare and probably does not exist. The case also definitely indicates that the organism reaches the central nervous system by way of nerve or perineural pathways.

Actinomycosis↗