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261 results on '"Cignarella G"'

3. Synthesis, Molecular Modeling and mu-Opioid Receptor Affinity of 9,10-Diazatricyclo[4.2.1.12,5] decanes and 2,7-Diazatricyclo[4.4.0.03,8]decanes Structurally Related to 3,8-Diazabicyclo[3.2.1]octanes

Author

VIANELLO P., ALBINATI A., PINNA G. A., BOREA P. A., GESSI S., FADDA P., TRONCI S., CIGNARELLA G., LAVECCHIA, ANTONIO, MARINELLI, LUCIANA, Vianello, P., Albinati, A., Pinna, G. A., Lavecchia, Antonio, Marinelli, Luciana, Borea, P. A., Gessi, S., Fadda, P., Tronci, S., and Cignarella, G.

Abstract

Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2. 1]octanes (DBO, 1) plays an essential role in modulating affinity toward mu opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N(3) propionyl, N(8) arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2. 1.1(2,5)]decane (4) and 2,7-diazatricyclo[4.4.0.0(3,8)]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest mu-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.

Published
2000

7. Structure-based design of an inhibitor modeled at the substrate active site of aldose reductase

Author

Rastelli, Giulio, Vianello, P., Barlocco, D., Costantino, Luca, Cignarella, G., DEL CORSO, A., and Mura, U.

Subjects
chemistry.chemical_classification, Aldose reductase, aldose reductase, molecular dynamics, docking, structure-based ligand design, biology, Molecular model, Stereochemistry, Carboxylic acid, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, Active site, Biochemistry, Molecular mechanics, chemistry, Enzyme inhibitor, Docking (molecular), Drug Discovery, biology.protein, Molecular Medicine, Molecular Biology, Aldehyde Reductase
Abstract

This study presents the first successful example of structure-based drug design on aldose reductase in the extant literature. Starting from the structure of the modeled complex of aldose reductase with a pyridazinone acetic acid inhibitor that we previously disclosed, using the tools of molecular modeling for structure manipulation and molecular mechanics for energy minimization, we were able to design and synthesize a new analog that showed remarkably improved activity. We hope that a proper account of the most important enzyme-inhibitor interactions revealed by this study will allow, in the future, the design of new lead compounds having structures unrelated to carboxylic acids.

Published
1997

8. Thienocycloheptapyridazines as new muscarinic agents

Author

Barlocco, D., Cignarella, G., Francesca Fanelli, Vitalis, B., Matyus, P., and Benedetti, P. G.

Subjects
Male, computational modeling, muscarinic receptors, Muscarinic Antagonists, Muscarinic Agonists, Receptors, Muscarinic, Drug design, GPCRs, Rats, Pyridazines, Rats, Sprague-Dawley, Structure-Activity Relationship, Animals, Humans
Abstract

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.

Published
1997

9. 2-(Substituted)amino-2,8-diazaspiro[4,5]decan-1,3-diones as potential muscarinic agonists: synthesis, modeling and binding studies

Author

Barlocco, D., Francesca Fanelli, Cignarella, G., Villa, S., Cattabeni, F., Balduini, W., Cimino, M., and Benedetti, P. G.

Subjects
Cerebral Cortex, Models, Molecular, computational modeling, muscarinic receptors, Protein Conformation, Succinimides, Muscarinic Agonists, Receptors, Muscarinic, Drug design, GPCRs, Rats, Quinuclidinyl Benzilate, Animals, Carbachol, Computer Simulation, Spiro Compounds
Abstract

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.

Published
1996

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