title: Design, Synthesis, and Biological Evaluation of Novel Tetrahydroprotoberberine Derivatives (THPBs) as Selective α1A-Adrenoceptor Antagonists.
abstract: A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as selective α1A-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 α1A-ARs, with IC50less than 250 nM. Among them, compound (S)-27 had the most potent biological activity; its IC50toward α1A-AR was 12.8 ± 2.2 nM, which is 781 and 20 times more selective than that toward α1B- and α1D-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 α1A-AR antagonists for the treatment of BPH.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Diliang
authors.initials: D
authors.lastname: Guo
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors.forename: Henry
authors.initials: H
authors.lastname: Lin
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Sun
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.|Department of Pharmacology, University of North Carolina Chapel Hill School of Medicine , Chapel Hill, North Carolina 27516, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.affiliation: Department of Natural Product Chemistry, School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shan
authors.affiliation: Department of Natural Product Chemistry, School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001600:Berberine Alkaloids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D001600:Berberine Alkaloids; D051638:Ether-A-Go-Go Potassium Channels; D018340:Receptors, Adrenergic, alpha-1; C014845:berbine