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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.

Authors+Show Affiliations

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -