2-Amino-3-aroyl-4,5-alkylthiophenes: Agonist allosteric enhancers at human A1 adenosine receptors

Tranberg, C. Elisabet, Zickgraf, Andrea, Giunta, Brian N., Luetjens, Henning, Figler, Heidi, Murphree, Lauren J., Falke, Ruediger, Fleischer, Holger, Linden, Joel, Scammells, Peter J. and Olsson, Ray. A. 2002, 2-Amino-3-aroyl-4,5-alkylthiophenes: Agonist allosteric enhancers at human A1 adenosine receptors, Journal of medicinal chemistry, vol. 45, no. 2, pp. 382-389, doi: 10.1021/jm010081p.

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Title 2-Amino-3-aroyl-4,5-alkylthiophenes: Agonist allosteric enhancers at human A1 adenosine receptors
Formatted title 2-Amino-3-aroyl-4,5-alkylthiophenes: Agonist allosteric enhancers at human A1 adenosine receptors
Author(s) Tranberg, C. Elisabet
Zickgraf, Andrea
Giunta, Brian N.
Luetjens, Henning
Figler, Heidi
Murphree, Lauren J.
Falke, Ruediger
Fleischer, Holger
Linden, Joel
Scammells, Peter J.
Olsson, Ray. A.
Journal name Journal of medicinal chemistry
Volume number 45
Issue number 2
Start page 382
End page 389
Publisher American Chemical Society
Place of publication Washington, D.C.
Publication date 2002-01-17
ISSN 0022-2623
Summary 2-Amino-3-benzoylthiophenes are allosteric enhancers (AE) of agonist activity at the A1 adenosine receptor. The present report describes syntheses and assays of the AE activity at the human A1AR (hA1AR) of a panel of compounds consisting of nine 2-amino-3-aroylthiophenes (3a-i), eight 2-amino-3-benzoyl-4,5-dimethylthiophenes (12a-h), three 3-aroyl-2-carboxy-4,5- dimethylthiophenes (15a-c), 10 2-amino-3-benzoyl-5,6-dihydro 4H-cyclopenta[b]thiophenes (17a-j), 14 2-amino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophenes (18a-n), and 15 2-amino- 3-benzoyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophenes (19a-o). An in vitro assay employing the A1AR agonist [125I]ABA and membranes from CHO-K1 cells stably expressing the hA1AR measured, as an index of AE activity, the ability of a candidate AE to stabilize the agonist- A1AR-G protein ternary complex. Compounds 3a-i had little or no AE activity, and compounds 12a-h had only modest activity, evidence that AE activity depended absolutely on the presence of at least a methyl group at C-4 and C-5. Compounds 17a-c lacked AE activity, suggesting the 2-amino group is essential. Polymethylene bridges linked thiophene C-4 and C-5 of compounds 17a-j, 18a-n, and 19a-o. AE activity increased with the size of the -(CH2)n- bridge, n ) 3 < n ) 4 < n ) 5. The 3-carbethoxy substituents of 17a, 18a, and 19a did not support AE activity, but a 3-aroyl group did. Bulky (or hydrophobic) substituents at the meta and para positions of the 3-benzoyl group and also 3-naphthoyl groups greatly enhanced activity. Thus, the hA1AR contains an allosteric binding site able to accommodate 3-aroyl substituents that are bulky and/or hydrophobic but not necessarily planar. A second region in the allosteric binding site interacts constructively with alkyl substituents at thiophene C-4 and/or C-5.
Language eng
DOI 10.1021/jm010081p
Field of Research 030499 Medicinal and Biomolecular Chemistry not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2002, American Chemical Society
Persistent URL http://hdl.handle.net/10536/DRO/DU:30001772

Document type: Journal Article
Collection: School of Biological and Chemical Sciences
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