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Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors.
Eur J Med Chem. 2012 Dec; 58:30-43.EJ

Abstract

Within our studies on structure-activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CB1) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K(i)(CB1) and K(i)(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl)amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CB1 receptor. Compounds 4 and 40, a CB2 and a CB1 ligand, respectively, behaved as partial agonists in the [(35)S]GTPγS assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood-brain barrier.

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Authors+Show Affiliations

Pasquini S
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.
De Rosa M
No affiliation info available
Ligresti A
No affiliation info available
Mugnaini C
No affiliation info available
Brizzi A
No affiliation info available
Caradonna NP
No affiliation info available
Cascio MG
No affiliation info available
Bolognini D
No affiliation info available
Pertwee RG
No affiliation info available
Di Marzo V
No affiliation info available
Corelli F
No affiliation info available

MeSH

AnimalsCHO CellsCell LineCricetinaeDogsDose-Response Relationship, DrugHumansLigandsMolecular StructureQuinolonesReceptor, Cannabinoid, CB1Receptor, Cannabinoid, CB2Structure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23085772

Citation

Pasquini, Serena, et al. "Investigations On the 4-quinolone-3-carboxylic Acid Motif. 6. Synthesis and Pharmacological Evaluation of 7-substituted Quinolone-3-carboxamide Derivatives as High Affinity Ligands for Cannabinoid Receptors." European Journal of Medicinal Chemistry, vol. 58, 2012, pp. 30-43.
Pasquini S, De Rosa M, Ligresti A, et al. Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors. Eur J Med Chem. 2012;58:30-43.
Pasquini, S., De Rosa, M., Ligresti, A., Mugnaini, C., Brizzi, A., Caradonna, N. P., Cascio, M. G., Bolognini, D., Pertwee, R. G., Di Marzo, V., & Corelli, F. (2012). Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors. European Journal of Medicinal Chemistry, 58, 30-43. https://doi.org/10.1016/j.ejmech.2012.09.035
Pasquini S, et al. Investigations On the 4-quinolone-3-carboxylic Acid Motif. 6. Synthesis and Pharmacological Evaluation of 7-substituted Quinolone-3-carboxamide Derivatives as High Affinity Ligands for Cannabinoid Receptors. Eur J Med Chem. 2012;58:30-43. PubMed PMID: 23085772.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors. AU - Pasquini,Serena, AU - De Rosa,Maria, AU - Ligresti,Alessia, AU - Mugnaini,Claudia, AU - Brizzi,Antonella, AU - Caradonna,Nicola P, AU - Cascio,Maria Grazia, AU - Bolognini,Daniele, AU - Pertwee,Roger G, AU - Di Marzo,Vincenzo, AU - Corelli,Federico, Y1 - 2012/10/03/ PY - 2012/07/23/received PY - 2012/09/21/revised PY - 2012/09/25/accepted PY - 2012/10/23/entrez PY - 2012/10/23/pubmed PY - 2013/5/17/medline SP - 30 EP - 43 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 58 N2 - Within our studies on structure-activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CB1) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K(i)(CB1) and K(i)(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl)amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CB1 receptor. Compounds 4 and 40, a CB2 and a CB1 ligand, respectively, behaved as partial agonists in the [(35)S]GTPγS assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood-brain barrier. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/23085772/Investigations_on_the_4_quinolone_3_carboxylic_acid_motif__6__Synthesis_and_pharmacological_evaluation_of_7_substituted_quinolone_3_carboxamide_derivatives_as_high_affinity_ligands_for_cannabinoid_receptors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(12)00574-0 DB - PRIME DP - Unbound Medicine ER -
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