Design, Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective α_1A-Adrenoceptor Antagonists

A novel series of tetrahydro­protoberberine derivatives (THPBs) were designed, synthesized, and evaluated as selective α_1A-adrenergic receptors (AR) antagonists for the treatment of benign prostatic hyperplasia. On the basis of the pharmacophore model of the marketed drug silodosin, THPBs were modified by introducing an indole segment into their core scaffolds. In calcium assays, 7 out of 32 compounds displayed excellent antagonistic activities against α_1A-ARs, with IC₅₀ less than 250 nM. Among them, compound (S)-27 had the most potent biological activity; its IC₅₀ toward α_1A-AR was 12.8 ± 2.2 nM, which is 781 and 20 times more selective than that toward α_1B- and α_1D-AR, respectively. In the functional assay using isolated rat tissues, compound (S)-27 inhibited norepinephrine-induced urethra smooth muscle contraction potently (IC₅₀ = 0.5 ± 0.3 nM), without inhibiting the aortic contraction (IC₅₀ > 1000 nM), displaying a better tissue selectivity than the marketed drug silodosin. Additional results of preliminary safety studies (acute toxicity and hERG inhibition) and pharmacokinetics studies indicated the potential druggability for compound (S)-27 which is a promising lead for the development of selective α_1A-AR antagonists for the treatment of BPH.