Elucidation of structure-activity relationships of 2-amino-3-benzoylthiophenes: Study of their allosteric enhancing vs. antagonistic activity on adenosine A(1) receptors

Novel 2-amino-3-benzoylthiophene derivatives, with variable substitution on the thiophene as well as benzoyl ring, were synthesized and evaluated both as allosteric enhancers of agonist binding to the rat adenosine A(1) recep tor, and as antagonists on this receptor. Structural features were identifi ed on the novel derivatives that favored allosteric enhancing activity, suc h as benzoyl lipophilic substitution and thiophene 4-alkyl substitution. In contrast, antagonistic properties were favored by thiophene 5-bulky substi tution. Upon further analysis, a significant correlation was found between antagonistic activity and hydrophobic fragment constants (pi values) of sub stituent R-5, in contrast to a negative correlation with those of R-4. Comp arison of low energy conformations of some of the 2-amino-3-benzoylthiophen e derivatives (PD81,723 and 4f) with known adenosine A(1) antagonists (theo phylline and 8-cyclo-hexyltheophylline) indicated that thiophene 5-substitu ents may interact with the same lipophilic domain of the adenosine A(1) rec eptor accommodating 8-substituents of xanthine antagonists. (C) 2000 Wiley- Liss, Inc.