Biomedical subjects

D Barlocco

Publications and source records attributed to D Barlocco.

At least 55 records · Page 3Linked to original sources

PubMed1997

Study of the antisecretory and antiulcer mechanisms of a new indenopirydazinone derivative in rats.

The present study investigates the antisecretory and antiulcer mechanisms of a new indenopyridazinone derivative previously reported to inhibit gastric acid secretion in pylorus-ligated rats and to prevent gastric ulcerations induced by indomethacin or ethanol in the same animal species. The new compound was tested on the acid hypersecretion induced by histamine, pentagastrin and bethanechol in in vivo and in vitro experimental models. Furthermore, its influence on the mucosal layer adhering the gastric wall in indomethacin-treated rats was considered. Ranitidine was selected as a reference drug. The results obtained demonstrated that the new molecule, at variance with ranitidine, exerts antiulcer activity mainly enhancing the gastric mucosal integrity and simultaneously inhibiting the gastric acid hypersecretion evoked exclusively by cholinergic pulses. Therefore, an involvement of a neuronal rather than an effectorial mechanism has been suggested. Due to these mechanisms of action it clearly differentiates from ranitidine and its possible application in the peptic disease resistant to H2-blockers could be speculated.

Animals↗

PubMed1997

Antinociceptive action of DBO 17 and DBO 11 in mice: two 3,8 diazabicyclo (3.2.1.) octane derivates with selective mu opioid receptor affinity.

Two 3,8 diazabicyclo (3.2.1.) octane derivates, namely DBO 17 and DBO 11, were studied for the opioid-like activity. In the rat brain membrane preparation binding studies, DBO 17 and DBO 11 showed a high affinity and selectivity for the mu opioid receptor (Ki's: 5.1 and 25 nM, respectively). DBO 17 and DBO 11 inhibited the nociceptive response in the hot-plate test of mice with ED50 values of 0.16 mg/kg and 0.44 mg/kg, respectively. The antinociceptive action of both DBO 17 and DBO 11 was blocked by naloxone. Tolerance to the antinociceptive action of DBO 17 and DBO 11 was present after 13 and 7 days of repeated treatment, respectively. Both DBO 17 and DBO 11 were ineffective in morphine-tolerant mice and vice versa. Chronic treatments (three times daily for seven consecutive days) of DBO 17 and DBO 11 induced a naloxone-precipitated withdrawal syndrome in DBO 17 treated mice similar to that in morphine treated mice, whereas in DBO 11 treated mice abstinence signs were virtually absent. These results indicate an interesting pharmacological profile that suggests these compounds as possible new candidates for the clinical treatment of pain.

Analgesia↗

PubMed1997

Thienocycloheptapyridazines as new muscarinic agents.

A series of thienocycloheptapyridazines (3aa-dd), structurally related to Minaprine, was synthesized and compounds tested for their affinity towards muscarinic receptors. All of them showed Ki values in the micromolar range towards both the antagonist 3H-QNB and the agonist 3H-OXO-M, thus indicating that they act as antagonists at the muscarinic receptors. Moreover a theoretical study was performed on their interaction behaviour with a three dimensional (3-D) model of the human m1 muscarinic receptor.

Animals↗

PubMed1997

Indenopyridazinone derivatives as potential antisecretory and antiulcer agents.

A series of substituted indenopyridazinones (4b-h) has been synthesized and tested for their antisecretory and antiulcer activity, in comparison with ranitidine, as reference drug. While the monomethoxy (4b-d), as well as the benzyloxy (4f) and the 6,9-dimethoxy (4g) derivatives were found to be devoid of overt antisecretory properties, the 9-methoxy (4e) was weakly active. The most interesting compound of this class was the 7,8-dimethoxy substituted (4h), which at an oral dose of 30 mg/kg still retains a significant activity. The dihydroderivatives of 4g,h (compounds 1g,h) were more active (1g) or comparable (1h) to the parent compounds, thus proving that the 4, 4a-double bond, which was an essential requirement in the analogues 2 and 3, is not necessary in this new series. The disubstituted derivatives (1g,h; 4g,h) were also tested as antiulcer agents, in two different models. All compounds were able to prevent haemorragic lesions induced in rats by 90% ethanol in a dose dependent manner. In the indomethacin model they still showed a significant activity, though lower than in the previous test. Attempts have been made to elucidate their mechanism of action.

Animals↗

PubMed1996

Synthesis, activity, and molecular modeling of a new series of tricyclic pyridazinones as selective aldose reductase inhibitors.

Three new series of tricyclic pyridazinones have been synthesized and tested in vitro in order to assess (i) their ability to inhibit aldose reductase enzyme (ALR2) and (ii) their specificity toward the target enzyme with respect to other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, and glutathione reductase. The inhibitory capability of the most effective compounds (IC50 values ranging from 6.44 to 12.6 microM) appears to be associated with a rather significant specificity for ALR2. Molecular mechanics and molecular dynamic calculations performed on the ALR2-inhibitor complex give indications of specific interaction sites responsible for the binding, thus providing information for the design of new inhibitors with improved affinity for the enzyme.

Aldehyde Reductase↗

PubMed1996

Conformational analysis of phthalein derivatives acting as thymidylate synthase inhibitors by means of 1H NMR and quantum chemical calculations.

The conformations of a set of phthalein derivatives with bacterial thymidylate synthase (TS) inhibitory activity were investigated by 1H NMR spectra, performed at both room and low temperature, and by quantum chemical calculations. Since the crystal structure of the binary complex of phenolphthalein with the enzyme is known, we set out to study the conformation of various of its analogues in solution in order to observe the effects of the substituents on the phenolic rings, of the alpha-naphthol derivative and of the rigid analogue, fluorescein, and compare the results with the X-ray crystal structure studies. A relationship between the chemical shift of the proton on C4 (H4) of the phthalidic ring and the averaged angle formed by the phthalidic and the aromatic ring planes was found in which the most perpendicular conformations have the lowest H4 chemical shift values. At room temperature, the rotational freedom of all the studied compounds was similar, while at lower temperature the naphthol derivative assumed a partially blocked conformation. Finally, a qualitative relationship between the inhibitory properties of the compounds and their conformations is discussed.

Coloring Agents↗

PubMed1996

2-(Substituted)amino-2,8-diazaspiro[4,5]decan-1,3-diones as potential muscarinic agonists: synthesis, modeling and binding studies.

A series of 2-(acyl)amino-8-substituted-2,8-diazaspiro[4,5]decan-1,3-diones (5a-j), structurally related to the muscarinic agonist RS-86, was synthesized and compounds tested for their affinity towards muscarinic receptors. Though all compounds proved to be less active than the model in binding studies, only three derivatives (5a, b, c) being able to significantly displace 3H-QNB at mM concentration, their behaviour could be interpreted in terms of theoretical molecular descriptors computed on the basis of the suggestions coming from Molecular Dynamics simulations of ligand-receptor complexes.

Animals↗

PubMed1995

Synthesis of 1,4-disubstituted-2-methylpiperazines and study of their analgesic properties.

A series of N,N-disubstituted-2-methylpiperazines (3a-e) has been synthesized and compounds tested both in vitro and in vivo for their analgesic properties. Binding studies showed that the new compounds are devoid of relevant affinity towards mu receptors. However, compound 3a displayed significant analgesic properties both in the hot plate test and in the mouse phenyl-p-benzoquinone induced abdominal constriction test (MAC), whereas the other derivatives were found active only in MAC test. Moreover, it should be noted that compound 3a elicited a Straub-tail reaction also at the lowest administered dose (10 mg/kg, ip) and this effect was antagonized by naloxone.

Analgesics↗

PubMed1993

Computer-aided structure-affinity relationships in a set of piperazine and 3,8-diazabicyclo[3.2.1]octane derivatives binding to the mu-opioid receptor.

Molecular modeling studies were carried out on a set of piperazine and 3,8-diazabicyclo[3.2.1]octane derivatives with the aim to highlight the main factors modulating their affinity for the mu-opioid receptor. Structure-affinity relationships were developed with the aid of molecular mechanics and semiempirical quantum-mechanics methods. According to our proposed pharmacodynamic model, the binding to the mu-receptor is promoted by the following physico-chemical features: the presence of hydrocarbon fragments on the nitrogen ring frame capable of interacting with one of two hypothesized hydrophobic receptor pockets; a 'correct' orientation of an N-propionyl side chain so as to avoid a sterically hindered region of the receptor; the possibility of accepting a hydrogen bond from a receptor site complementary to the morphine phenol oxygen.

Bridged Bicyclo Compounds↗

PubMed1993

Synthesis and pharmacological evaluation of a new class of 2-oxo-8-azaspiro (4,5)decan-1-ones as analogues of the muscarinic agonist RS-86.

A new series of 8-substituted-2-oxo-8-azaspiro (4,5)decan-1-ones has been synthesized and compounds tested for their cholinergic properties in comparison with the muscarinic agonist RS-86. Preliminary in vitro and in vivo pharmacological data indicate that none of them is provided with significant cholinergic effects either at central or peripheral level. A possible explanation for the lack of activity is given on the basis of conformational studies.

Animals↗

PubMed1993

Synthesis and opioid receptor affinity of bivalent ligands derived from 3,8-diazabicyclo(3.2.1)octanes.

A new series of bivalent ligands (2a-d), derived from the previously reported analgesic 3-cinnamyl-8-propionyl-3,8-diazabicyclo(3.2.1)octane (1a), has been synthesized and tested in vitro for their affinity towards opioid receptors and in vivo for their analgesic potency. None of the new compounds showed either appreciable affinity for opioid receptors or analgesic activity comparable to that of the model 1a.

Analgesics↗

PubMed1992

Synthesis and pharmacological activity of 4-carbamoyl-5-aryl-6-methyl-4,5-dihydropyridazin-3(2H)-ones.

A new series of 4-carbamoyl-5-aryl-6-methyl-4,5-dihydropyridazin-3(2H)-ones have been synthesized and tested for their antiinflammatory and analgesic properties. Amongst the test compounds, only 31 showed antiinflammatory activity, though of shorter duration than that of indomethacin, taken as reference drug. On the contrary, many derivatives displayed relevant analgesic activity, 4--the only 4,5-dehydroderivative--being the most potent in the writhing test. In the hot plate test 3b, 3f and 3k were found to possess the most significant analgesic properties.

Animals↗

PubMed1991

Diuretic agents related to indapamide. IV--Synthesis and pharmacological activity of N-(4-chloro-3-sulfamoylbenzamido)-methyl-phenyl-pyrrolidines and N1-(4-chloro-3-sulfamoylbenzoyl)-N2-aryl- or aralkyl-alkyl-hydrazines.

A series of N(4-chloro-3-sulfamoylbenzamido) derivatives (6 a-c, 10, 11, 12), structurally related to indapamide and isoindapamide, were synthesized and tested for their diuretic and saluretic activity. In addition, the antihypertensive activity of the most interesting term trans 6a was studied on spontaneously hypertensive rats. All tested compounds with the exception of 10 showed diuretic activity comparable to or higher (trans 6 a) than that of indapamide, taken as reference drug. The antihypertensive activity of trans 6 a was comparable to that of indapamide in potency, but its onset of action was slower.

Animals↗

PubMed1990

Conformationally constrained congeners of 6-aryl-5-methyl-4,5-dihydro-3(2H)-pyridazinones active on the cardiovascular system: conformational studies by molecular mechanics calculations and 1H NMR spectroscopy.

Unsubstituted phenylpyridazinones 1a and 2a and their tricyclic analogues indenopyridazinone 3a, benzocinnolinone 4a, and benzocycloheptapyridazinone 5a were submitted to conformational analysis with Allinger's MM2(85) program in order to better define the relationship between the cardiovascular properties of some derivatives and their preferred conformations. Structures 1-4, giving rise to highly active compounds, were found to exist in a conformation showing a near-planar arrangement of the phenyl and the pyridazinone ring. On the contrary, 5, whose derivatives were inactive, shows two significantly populated conformations both markedly deviated from planarity. 1H NMR analysis of the tricyclic systems 3-5 was in full agreement with the molecular mechanics calculations.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1989

Synthesis and biological evaluation of substituted benzo[h]cinnolinones and 3H-benzo[6,7]cyclohepta[1,2-c]pyridazinones: higher homologues of the antihypertensive and antithrombotic 5H-indeno[1,2-c]pyridazinones.

Several substituted benzo[h]cinnolinones 3 and 3H-benzo[6,7]cyclohepta[1,2-c]pyridazinones 4, which were designed as less rigid congeners of 5H-indeno[1,2-c]pyridazinones 2, were synthesized and tested as antihypertensive, inotropic, antithrombotic, antiinflammatory, and antiulcer agents. While the seven-membered ring derivatives displayed only antithrombotic properties, which were comparable to that of acetylsalicylic acid, most of the benzo[h]cinnolinones exhibited significant antihypertensive, inotropic, and antithrombotic properties. In this respect, the 8-amino (3b) and 8-acetylamino (3c) together with the 4,4a-dehydro analogue of 3c (11) were found to possess the most potent and long-lasting antihypertensive activity. In particular, the dextro isomer of 3c was more active than the racemic form, with lower tachycardiac effects. Unlike the lower homologues 2, none of the compounds showed significant antiinflammatory or antiulcer activity.

Animals↗

PubMed1989

Synthesis and pharmacological study of 4,4a,5,6-tetrahydro-4a-substituted-benzo(h)cinnolin-3(2H)ones.

A series of 4,4a,5,6- tetrahydro-4a-substituted-benzo(h)cinnolin-3(2H)-one (II a-e) (III a) were synthesized and evaluated pharmacologically in comparison with the 4a-unsubstituted congeners (I), which were reported to be potent antithrombotic and antihypertensive agents. All the test compounds, apart from (II e) (R2 = OCH3) and (III a) (R1,R2 = H), displayed significant antihypertensive activity. In particular (II a) (R1,R2 = H) was more active than the unsubstituted analogue (I a). Moreover (II d) (R1 = OCH3), (II e) (R2 = OCH3) and (III a) showed antithrombotic activity comparable to or higher than that of ASA.

Animals↗

PubMed1989

Diuretic agents related to indapamide. III--Synthesis and pharmacological activity of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydroisoquinolines.

A series of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinoline++ + (IV-1) and isoquinoline (IV-2) have been synthesized and their diuretic and antihypertensive activities evaluated. While none of the test compounds was found to be provided with antihypertensive properties, most of them displayed a diuretic activity comparable to (IV-2 a) or higher (IV-1 a,b) (IV-2 c) than those of indapamide and clopamide, taken as reference drugs.

Animals↗

PubMed1988

Interaction of 3,8-diazabicyclo (3.2.1) octanes with mu and delta opioid receptors.

A series of 3,8-diazabicyclo (3.2.1) octanes (DBO) (1) substituted at the nitrogen atoms by acyl and aralkenyl groups, were tested in in vitro binding assays towards mu and delta opioid receptors. The most representative terms (1a, 1d, 1g, 1j,) were also evaluated for the analgesic potency in vivo by the hot plate method. Among the compounds tested the most potent was the p.nitrocinnamyl DBO (1d) which displayed a mu/delta selectivity and an analgesic activity respectively 25 and 17 fold those of morphine. On the contrary, the m.hydroxycinnamyl DBO (1g) was markedly less active as agonist than the parent 1a, thus suggesting that structure 1 interacts with opioid receptors in a different fashion than morphine. Compound 1j isomer of 1a which is provided with high mu affinity, but lower analgesic potency, was found to possess a mixed agonist-antagonist activity.

Animals↗