Elucidation of structure–activity relationships of 2‐amino‐3‐benzoylthiophenes: Study of their allosteric enhancing vs. antagonistic activity on adenosine A1 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 A₁ receptor, and as antagonists on this receptor. Structural features were identified on the novel derivatives that favored allosteric enhancing activity, such as benzoyl lipophilic substitution and thiophene 4‐alkyl substitution. In contrast, antagonistic properties were favored by thiophene 5‐bulky substitution. Upon further analysis, a significant correlation was found between antagonistic activity and hydrophobic fragment constants (π values) of substituent R⁵, in contrast to a negative correlation with those of R⁴. Comparison of low energy conformations of some of the 2‐amino‐3‐benzoylthiophene derivatives (PD81,723 and 4f) with known adenosine A₁ antagonists (theophylline and 8‐cyclohexyltheophylline) indicated that thiophene 5‐substituents may interact with the same lipophilic domain of the adenosine A₁ receptor accommodating 8‐substituents of xanthine antagonists. Drug Dev. Res. 49:227–237, 2000. © 2000 Wiley‐Liss, Inc.