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Clementina Manera

Publications and source records attributed to Clementina Manera.

13 recordsLinked to original sources
PubMed2006

Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists.

On the basis of docking studies carried out using the recently published cannabinoid receptor models,35 new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, which presented p-fluorobenzyl and carboxycycloheptylamide substituents bound in the 1 and 3 positions of the 1,8-naphthyiridine-4-one nucleus, showed a high CB2 affinity with a Ki of 1.0 nM. The substitution of the naphthyridine-4-one nucleus with the quinoline-4-one system determined a general increase in CB2 affinity. In particular, the N-cyclohexyl-7-chloro-1-(2-morpholin-4-ylethyl)quinolin-4(1H)-on-3-carboxamide (40) possessed a remarkable affinity, with Ki of 3.3 nM, which was also accompanied by a high selectivity for the CB2 receptor (Ki(CB1)/Ki(CB2) ratio greater than 303). Moreover, the [35S]GTPgamma binding assay and functional studies on human basophils indicated that the 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives behaved as CB1 and CB2 receptor agonists.

Amides↗
PubMed2006

Cannabinoid CB2/CB1 selectivity. Receptor modeling and automated docking analysis.

Three-dimensional models of the CB1 and CB2 cannabinoid receptors were constructed by means of a molecular modeling procedure, using the X-ray structure of bovine rhodopsin as the initial template, and taking into account the available site-directed mutagenesis data. The cannabinoid system was studied by means of docking techniques. An analysis of the interaction of WIN55212-2 with both receptors showed that CB2/CB1 selectivity is mainly determined by the interaction in the CB2 with the nonconserved residues S3.31 and F5.46, whose importance was suggested by site-directed mutagenesis data. We also carried out an automated docking of several ligands into the CB2 model, using the AUTODOCK 3.0 program; the good correlation obtained between the estimated free energy binding and the experimental binding data confirmed our binding hypothesis and the reliability of the model.

Amino Acid Sequence↗
PubMed2006

Adenosine receptor modelling. A1/A2a selectivity.

Three-dimensional models of the A(1) and A(2a) adenosine receptors (AR) were constructed by means of a homology procedure, using bovine rhodopsin as a template. In order to validate the two models, a docking analysis of selective agonists was carried out. The study shows that A(1)/A(2a) selectivity is mainly influenced by the different ability of the two receptors to give lipophilic interactions, instead of giving different H bonds. The binding site cavity of the A(1)AR is smaller than that of the A(2a)AR, and for this reason, less bulky ligands like CPA are able to give close interactions with the A(1)AR, unlike larger ligands such as CGS-21680. The different dimensions of the binding site cavity could be due to the presence of three residues of proline, which cause a different rearrangement of the TM, thus modifying the side chain disposition inside the inter-helix channel.

Adenosine↗
PubMed2005

1,8-Naphthyridin-4-one derivatives as new ligands of A2A adenosine receptors.

A series of 1,8-naphthyridine derivatives bearing various substituents in position 3, 4, and 7 of the heterocyclic nucleus have been synthesized and evaluated for their affinity at the bovine and human adenosine receptors. The new compounds were found to lack the affinity toward A(1)AR, whereas many of them are able to acquire an interesting affinity and selectivity for the A(2A)AR.

Animals↗
PubMed2004

Study on affinity profile toward native human and bovine adenosine receptors of a series of 1,8-naphthyridine derivatives.

A new series of 1,8-naphthyridine derivatives (29-44 and 46-52) bearing various substituents in different positions on the heterocyclic nucleus were synthesized in order to analyze the effects produced on the affinity toward the bovine adenosine receptors. These derivatives represent an extension of our previous work on this class of compounds with high affinity toward A(1) adenosine receptors.(19) The results of radioligand binding assays indicate that a large number of the 1,8-naphthyridine derivatives proved to be A(1) selective, with a high affinity toward bovine adenosine receptors in the low nanomolar range, and one (29) in the subnanomolar range. Furthermore, the new series of 1,8-naphthyridine derivatives (29-44 and 46-52), together with the analogous derivatives 1-28 previously studied,(19) were tested to evaluate their affinity toward human cortical A(1) receptors and human striatal A(2A) receptors. The results indicate that all the 1,8-naphthyridine compounds generally possess a higher affinity toward the bovine A(1) receptor compared with the human A(1) receptor. As regards the affinity toward the A(2A) bovine receptor, only a few compounds possess a moderate affinity, which for some compounds remained approximately the same toward the A(2A) human receptor. A molecular modeling study of the docking of the 1,8-naphthyridine compounds with both the bovine and the human A(1) adenosine receptors was carried out with the aim of explaining the marked decrease in the affinity toward human A(1) adenosine receptors in comparison with bovine A(1) adenosine receptors. This study indicated that the structural differences, albeit small, of the active sites of the two receptors make differences in the dimensions of the site and this influenced the ability of the title compounds to interact with the two A(1) receptors.

Animals↗
PubMed2004

Synthesis and biological evaluation of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives as new ligands of cannabinoid receptors.

Cannabinoid receptors have been studied extensively in view of their potential functional role in several physiological and pathological processes. For this reason, the search for new potent, selective ligands for subtype CB receptors, CB(1) and CB(2), is still of great importance, in order to investigate their role in various physiological functions. The present study describes the synthesis and the biological properties of a series of 1,8-naphthyridine derivatives, characterised by the presence of some important structural requirements exhibited by other classes of cannabinoid ligands, such as an aliphatic or aromatic carboxamide group in position 3, and an alkyl or arylalkyl substituent in position 1. These compounds were assayed for binding both to the brain and to peripheral cannabinoid receptors (CB(1) and CB(2)). The results obtained indicate that the naphthyridine derivatives examined possess a greater affinity for the CB(2) receptor than for the CB(1) receptor. In particular, derivatives 6a and 7a possess an appreciable affinity for the CB(2) receptor, with K(i) values of 5.5 and 8.0 nM respectively; also compounds 4a, 5a and 8a exhibit a good CB(2) affinity, with K(i) values in the range of 10-44 nM. Furthermore, compounds 3g-i and 18 revealed a good CB(2) selectivity, with a CB(1)/CB(2) ratio >20.

Animals↗
PubMed2003

Synthesis and beta-blocking activity of (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2,3-b]pyridine: identification of beta 3-antagonists.

Drugs acting on beta(1)- and beta(2)-adrenergic receptors are widely used for the clinical management of a large number of cardiovascular and respiratory pathologies. In the last decade, the discovery of the third subtype of beta receptors, the beta(3)-adrenoceptor, gave a further pharmacological target for the development of new selective drugs. Initially, a potential therapeutic use of beta(3)-selective agents seemed to be restricted to agonists, for the treatment of metabolic diseases, such as obesity, non-insulin-dependent diabetes, urinary frequency and incontinence. More recently, some interesting theories about a negative role played by the cardio-depressant activity of myocardial beta(3)-adrenoceptors in heart failure, seemed to justify a clinical use of beta(3)-antagonists in the last phases of this cardiac disease. Following the indications deriving from previous experimental work, the beta-antagonist properties of newly-synthesised (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and of 2,3-dihydrothiopyrano[2,3-b]pyridine were evaluated, in order to identify some useful structure-activity relationships, which might account for selectivity towards the three beta-subtypes and, in particular, the beta(3)-adrenoceptor. Among the various observations regarding possible structure-activity relationships, able to explain the pharmacodynamic patterns of the synthesised compounds on the three subtypes of beta-adrenoceptors, the most significant data derived from the evaluation of the beta(3)-blocking properties of some oximeethers of 1,8-naphthyridine derivatives. In these molecules, although the presence of the large substituents in position 7, such as 4-chloro-phenoxy- or 4-t-butyl-phenoxy groups determined a dramatic decline in both the beta(1)- and beta(2)-activities, this structural characteristic had a modest influence on the beta(3)-affinity, which was only slightly lower. Hence, this last structural requirement of oximeethers of 1,8-naphthyridine derivatives seems to represent a useful expedient to induce an appreciable selectivity towards the beta(3)-receptor, through a markedly negative effect on the beta(1)- and beta(2)-activities rather than an increase in the beta(3)-affinity.

Adrenergic beta-Antagonists↗
PubMed2003

Synthesis of 3- or 4-phenyl-1,8-naphthyridine derivatives and evaluation of antimycobacterial and antimicrobial activity.

A series of 3- or 4-phenyl-1,8-naphthyridine derivatives variously substituted in the positions 2, 6 and 7 were synthesized and evaluated for in vitro evaluation for their antimycobacterial activity as part of a TAACF TB screening program under the direction of the US National Institute of Health, NIAID division. Several compounds showed an interesting activity when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H(37)Rv and in particular compounds 2a, 4a,d, 8a,d and 8i, exhibit a % inhibition from 91 to 99. Among these, compounds 2a, 8a and 8d appeared to have a good activity with minimum inhibitory concentrations (MICs) of 6.25 microg/ml. On the basis of the biological results, the most effective substituent in position 2 or 7 seems to be the piperidinyl group. The introduction of a morpholinyl group either in position 2 or 7 of the heterocycle ring caused a decrease in activity. The 1,8-naphthyridine derivatives were also tested in vitro for their antimicrobial activity against Staphylococcus aureus as Gram-positive bacteria and Escherichia coli as Gram-negative bacteria.

Anti-Bacterial Agents↗
PubMed2002

Synthesis of variously substituted 1,8-naphthyridine derivatives and evaluation of their antimycobacterial activity.

A series of 1,8-naphthyridine derivatives variously substituted in the 2, 3, 4 and 7 positions were synthesized for in vitro evaluation of antimycobacterial activity in accordance with an international program with the tuberculosis antimicrobial acquisition and coordinating facility (TAACF). Several compounds 4, 8, 12, 14, 19, 29 and 30, when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H37Rv, showed an interesting activity with % inhibition in the range 38-96%. The most effective substituent in position 2, 4 or 7 of the 1,8-naphthyridine nucleus seem to be the piperidinyl group.

Anti-Bacterial Agents↗
PubMed2002

Conformationally restrained analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-2',5'-morpholines].

The 5,6- (10a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-)-2',5'-morpholine](11a) and their N-isopropyl derivatives (10b and 11b) (DDSNMs), which can be viewed as the result of the combination of the structure of the 2-(3,4-dihydroxyphenyl)morpholine 5a or 5b (DPMs) with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy- (8a or 8b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydro-1-naphthalen-ol (9a or 9b) (1-AMDTNs) were synthesised. The new compounds DDSNMs 10a,b and 11a,b were assayed for their alpha- and beta-adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described morpholine (5) and tetrahydronaphthalene (8, 9) derivatives. The affinity and activity indices thus obtained indicate in general a low ability of the new compounds 10 and 11 to interact with the alpha- and beta-adrenoceptors, which, in all cases, was lower than that of the corresponding morpholine (5) and tetrahydronaphthalene (8, 9) analogues.

Adrenergic Agonists↗
PubMed2002

Spirotetrahydronaphthalene analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3'-piperidines].

The 5,6- (5a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1 (2H)-3'-piperidine] (6a) and their N-isopropyl derivatives (5b and 6b), DDSNPs, were synthesized. These compounds can be viewed as the result of the combination of the structure of the 3-(3,4-dihydroxyphenyl)-piperidine 2a or 2b, with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy-(3a or 3b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (4a or 4b), 1-AMDTNs. The new compounds (5a, b and 6a, b) were assayed for their alpha and beta adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described 3-(3,4-dihydroxyphenyl)piperidine (3-DPP; 2) and 1-AMDTNs (3, 4). Comparison of the affinity and activity data of novel derivatives with those of reference compounds 2, 3 and 4 shows a general low ability of DDSNPs 5 and 6 to interact with both alpha and beta- adrenoceptors.

Animals↗
PubMedDate not supplied

Use of capillary electrophoresis and poly(ethylene oxide) as the coating agent for the determination of substances related to heroin addiction and treatment.

The purpose of this study was to identify and quantify morphine, codeine, methadone, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine using capillary electrophoresis in urine specimens. Adequate peak separation was achieved using nearly neutral pH phosphate buffer and poly(ethylene oxide) as the coating agent. This dynamic coating of the inner surface of the capillary was obtained by rinsing with a solution containing this compound. The electroosmotic flow and the interactions between analytes and the capillary wall surface were reduced, while resolution and reproducibility were thus improved. Detection limits were appropriate for usual analytical requirements in forensic laboratories.

Codeine↗