Modulation of A2B adenosine receptor by 1-Benzyl-3-ketoindole derivatives

被引：26

作者：

Taliani, Sabrina ^{[1
]}

Trincavelli, Maria Letizia ^{[1
]}

Cosimelli, Barbara ^{[2
]}

Laneri, Sonia ^{[2
]}

Severi, Elda ^{[2
]}

Barresi, Elisabetta ^{[1
]}

Pugliesi, Isabella ^{[1
]}

Daniele, Simona ^{[2
]}

Giacomelli, Chiara ^{[2
]}

Greco, Giovanni ^{[2
]}

Novellino, Ettore ^{[2
]}

Martini, Claudia ^{[1
]}

Da Settimo, Federico ^{[1
]}

机构：

[1] Univ Pisa, Dipartimento Farm, I-56126 Pisa, Italy

[2] Univ Naples Federico II, Dipartimento Farm, I-80131 Naples, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 69卷

关键词：

1-Benzyl-3-ketoindole derivatives; A(2B) adenosine receptor; Positive modulators; Negative modulators; GPCR modulators; Ligand-receptor interaction; BENZODIAZEPINE-RECEPTOR; HIGH-AFFINITY; ALLOSTERIC MODULATION; INTERNATIONAL UNION; EPITHELIAL-CELLS; A2B RECEPTOR; ANTAGONISTS; LIGANDS; A(2A); SITE;

D O I：

10.1016/j.ejmech.2013.09.001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We have disclosed a series of 1-benzyl-3-ketoindole derivatives acting as either positive or negative modulators of the human A2B adenosine receptor (A(2B) AR) depending on small differences in their side chain. The new compounds were designed taking into account structural similarities between AR antagonists and ligands of the GABAA/benzodiazepine receptor. All compounds resulted totally inactive at A(2A) and A(3) ARs and showed small (8a,b) or none (7a,b, 8c and 9a,b) affinity for A(1) AR. When tested on A(2B) AR-transfected CHO cells, 7a,b and 8a acted as positive modulators, whereas 8b,c and 9a,b acted as negative modulators, enhancing or weakening the NECA-induced increase of cAMP levels, respectively. Compounds 7-9 might be regarded as useful biological and pharmacological tools to explore the therapeutic potential of A(2B) AR modulators, while their 3-ketoindole scaffold might be taken as a reference to design new analogs. (C) 2013 Elsevier Masson SAS. All rights reserved.

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收藏

页码：331 / 337

页数：7

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[1] A2B receptor activation promotes glycogen synthesis in astrocytes through modulation of gene expression [J].

Allaman, I ;

Lengacher, S ;

Magistretti, PJ ;

Pellerin, L .

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2003, 284 (03) :C696-C704

[2] Recent improvements in the development of A2B adenosine receptor agonists [J].

Baraldi, Pier Giovanni ;

Tabrizi, Mojgan Aghazadeh ;

Fruttarolo, Francesca ;

Romagnoli, Romeo ;

Preti, Delia .

PURINERGIC SIGNALLING, 2009, 5 (01) :3-19

[3] Why are A2B receptors low-affinity adenosine receptors?: Mutation of Asn273 to Tyr increases affinity of human A2B receptor for 2-(1-hexynyl) adenosine [J].

Beukers, MW ;

Den Dulk, H ;

Van Tilburg, EW ;

Brouwer, J ;

Ijzerman, AP .

MOLECULAR PHARMACOLOGY, 2000, 58 (06) :1349-1356

[4]

Castelhano A.L., 2003, PCT Int. Appl., Patent No. [WO 2003053361, 2003053361]

[5] From the Pharmacophore to the Homology Model of the Benzodiazepine Receptor: The Indolyglyoxylamides Affair [J].

Cosimelli, Barbara ;

Cosconati, Sandro ;

Marinelli, Luciana ;

Novellino, Ettore ;

Greco, Giovanni .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2012, 12 (04) :321-332

[6] N′-phenylindol-3-ylglyoxylohydrazide derivatives:: Synthesis, structure-activity relationships, molecular modeling studies, and pharmacological action on brain benzodiazepine receptors [J].

Da Settimo, A ;

Primofiore, G ;

Da Settimo, F ;

Marini, AM ;

Novellino, E ;

Greco, G ;

Gesi, M ;

Martini, C ;

Giannaccini, G ;

Lucacchini, A .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (20) :3821-3830

[7] A1 adenosine receptor antagonists, 3-aryl [1,2,4]triazino[4,3-a]benzimidazol-4-(10H)-ones (ATBIs) and N-alkyl and N-acyl-(7-substituted-2-phenylimidazo[1,2-a][1,3,5]triazin-4-yl)amines (ITAs):: Different recognition of bovine and human binding sites [J].

Da Settimo, F ;

Primofiore, G ;

Taliani, S ;

La Motta, C ;

Novellino, E ;

Greco, G ;

Lavecchia, A ;

Cosimelli, B ;

Iadanza, M ;

Klotz, KN ;

Tuscano, D ;

Trincavelli, ML ;

Martini, C .

DRUG DEVELOPMENT RESEARCH, 2004, 63 (01) :1-7

[8] 3-aryl[1,2,4]triazino[4,3-α]benzimidazol-4(10H)-ones:: A new class of selective A1 adenosine receptor antagonists [J].

Da Settimo, F ;

Primofiore, G ;

Taliani, S ;

Marini, AM ;

La Motta, C ;

Novellino, E ;

Greco, G ;

Lavecchia, A ;

Trincavelli, L ;

Martini, C .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (03) :316-327

[9] Synthesis, structure-activity relationships, and molecular modeling studies of N-(indol-3-ylglyoxylyl)benzylamine derivatives acting at the benzodiazepine receptor [J].

DaSettimo, A ;

Primofiore, G ;

DaSettimo, F ;

Marini, AM ;

Novellino, E ;

Greco, G ;

Martini, C ;

Giannaccini, G ;

Lucacchini, A .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (26) :5083-5091

[10] Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist [J].

Eastwood, Paul ;

Esteve, Cristina ;

Gonzalez, Jacob ;

Fonquerna, Silvia ;

Aiguade, Josep ;

Carranco, Ines ;

Domenech, Teresa ;

Aparici, Monica ;

Miralpeix, Montserrat ;

Alberti, Joan ;

Cordoba, Monica ;

Fernandez, Raquel ;

Pont, Merce ;

Godessart, Nuria ;

Prats, Neus ;

Isabel Loza, Maria ;

Isabel Cadavid, Maria ;

Nueda, Arsenio ;

Vidal, Bernat .

ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (03) :213-218

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