α₁-Adrenoceptors as potential therapeutic targets

Design and Synthesis of anα1a‐Adrenergic Receptor Subtype‐Selective Antagonist from BE2254

“…Using cloned human α 1 ‐adrenergic receptors as research probes, we have discovered that many known α 1 ‐adrenergic receptor antagonists that have been used as BPH drugs have virtually no selectivity for any particular α 1 ‐adrenergic receptor subtype. We have also successfully demonstrated that the α 1a ‐adrenergic receptor is the receptor subtype that mediates human prostatic smooth muscle contraction (7), hence presenting itself as an ideal target for the development of new BPH drugs with less side‐effects (8–12).…”

“…We then shifted our attention to the substituent effects at the 3-position. From a limited set of analogs (8)(9)(10)(11), it is clear that little advantage could be gained at this position. Finally, several 3,4-disubstituted analogs were synthesized and tested; among them, only the 3,4-dimethoxy compound (13) fulfilled our requirements.…”

α1a/1d-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms

“…These results, combined with the fact that a moderately α 1a/1d -selective drug, tamsulosin (1), is capable of treating both BPH and LUTS, led to the formation of new hypothesis. Rather than targeting a nonselective or pure α 1a -selective drug, an antagonist with a balanced α 1a/1d selectivity profile should be efficacious yet produce less side effects, and hence render optimum benefit for BPH/LUTS patients [26][27][28][29][30]. Unfortunately, convincing proof for this hypothesis has been lacking because discovery of α 1 -blocking compound with high α 1a/1d selectivity is a very challenging task.…”