Hong Liu
Shanghai Institute of Materia Medica, China
Title: Design, synthesis and bioactivity evaluation of multi-targeted tetrahydroprotoberberine derivatives (THPBs)
Biography
Biography: Hong Liu
Abstract
Tetrahydroprotoberberines (THPBs) belong to a class of tetrahydroisoquinoline alkaloids with multiple bioactivities derived
mainly from Chinese medicinal herbs. An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of THPBs including l-stepholidine (l-SPD) was developed. A series of new THPB derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D1 and D2) and serotonin (5-HT1A and
5-HT2A) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D1 receptor, as well as high selectivity for the D1 receptor over the D2, 5-HT1A, and 5-HT2A receptors. 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 compounds displayed excellent antagonistic activities against α1A-ARs, with IC50 less than 250 nM. In the functional assay using isolated rat tissues, compound (S)-27 inhibited norepinephrineinduced urethra smooth muscle contraction potently, without inhibiting the aortic contraction, displaying a better tissue selectivity than the marketed drug silodosin. Additional results of preliminary safety studies and pharmacokinetics studies indicated the potential druggability for compound (S)-27 which is a promising lead for the development of selective α1A-AR antagonists for the treatment of Benign Prostatic Hyperplasia (BPH).