Bioisosteric phentolamine analogs as selective human α2- versus α1-adrenoceptor ligands

Phentolamine is known to act as a competitive, non-subtype-selective α-adrenoceptor antagonist. In an attempt to improve α2- versus α1-adrenoceptor selectivity and α2-adrenoceptor subtype-selectivity, two new chemical series of bioisosteric phentolamine analogs were prepared and evaluated. These compounds were evaluated for binding affinities on α1- (α1A-, α1B-, α1D-) and α2- (α2A-, α2B-, α2C-) adrenoceptor subtypes that had been stably expressed in human embryonic kidney and Chinese hamster ovary cell lines, respectively. Methylation of the phenolic hydroxy group and replacement of the 4-methyl group of phentolamine with varying lipophilic substituents yielded bioisosteric analogs selective for the α2- versus α1-adrenoceptors. Within the α2-adrenoceptors, these analogs bound with higher affinity at the α2A- and α2C-subtypes as compared to the α2B-subtype. In particular, the t-butyl analog was found to be the most selective, its binding at the α2C-adrenoceptor (Ki = 3.6 nM) being 37- to 173-fold higher than that at the α1-adrenoceptors, and around 2- and 19-fold higher than at the α2A- and α2B-adrenoceptors, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities of selected compounds from the bioisosteric series on human α1A- and α2C-adrenoceptors. Thus, the results with these bioisosteric analogs of phentolamine provide a lead to the rational design of potent and selective α2-adrenoceptor ligands that may be useful in improving the therapeutic profile of this drug class for human disorders.