title: 2-Amino-3-aroyl-4,5-alkylthiophenes: agonist allosteric enhancers at human A(1) adenosine receptors.
abstract: 2-Amino-3-benzoylthiophenes are allosteric enhancers (AE) of agonist activity at the A(1) adenosine receptor. The present report describes syntheses and assays of the AE activity at the human A(1)AR (hA(1)AR) 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 A(1)AR agonist [(125)I]ABA and membranes from CHO-K1 cells stably expressing the hA(1)AR measured, as an index of AE activity, the ability of a candidate AE to stabilize the agonist-A(1)AR-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 -(CH(2))(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 hA(1)AR 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.
authors.affiliation: Centre for Chiral and Molecular Technologies, Deakin University, Geelong, Victoria 3217, Australia.
authors.forename: C Elisabet
authors.initials: CE
authors.lastname: Tranberg
authors.forename: Andrea
authors.initials: A
authors.lastname: Zickgraf
authors.forename: Brian N
authors.initials: BN
authors.lastname: Giunta
authors.forename: Henning
authors.initials: H
authors.lastname: Luetjens
authors.forename: Heidi
authors.initials: H
authors.lastname: Figler
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Murphree
authors.forename: Ruediger
authors.initials: R
authors.lastname: Falke
authors.forename: Holger
authors.initials: H
authors.lastname: Fleischer
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.forename: Ray A
authors.initials: RA
authors.lastname: Olsson
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D058906:Purinergic P1 Receptor Agonists; D021281:Quantitative Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058906:Purinergic P1 Receptor Agonists; D013876:Thiophenes