2. Academic Validation
  3. Discovery of Selective Dopamine Receptor Ligands Derived from (-)-Stepholidine via C-3 Alkoxylation and C-3/C-9 Dialkoxylation

Discovery of Selective Dopamine Receptor Ligands Derived from (-)-Stepholidine via C-3 Alkoxylation and C-3/C-9 Dialkoxylation

  • J Med Chem. 2023 Jul 27;66(14):10060-10079. doi: 10.1021/acs.jmedchem.3c00976.
Hari K Namballa 1,  Michael Dorogan 1,  Ashok R Gudipally 1 2,  Sunday Okafor 3 4,  Satishkumar Gadhiya 1 2 5,  Wayne W Harding 1 2 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, New York, New York 10065, United States.
  • 2 Ph.D. Program in Chemistry, CUNY Graduate Center, 365 5th Avenue, New York, New York 10016, United States.
  • 3 Department of Pharmaceutical and Medicinal Chemistry, University of Nigeria, 410011 Nsukka, Enugu State, Nigeria.
  • 4 Center for Biomedical Research, New York, New York 10065, United States.
  • 5 Ph.D. Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, New York 10016, United States.
PMID: 37421373 DOI: 10.1021/acs.jmedchem.3c00976
Abstract

We evaluated C-3 alkoxylated and C-3/C-9 dialkoxylated (-)-stepholidine analogues to probe the tolerance at the C-3 and C-9 positions of the tetrahydroprotoberberine (THPB) template toward affinity for dopamine receptors. A C-9 ethoxyl substituent appears optimal for D1R affinity since high D1R affinities were observed for compounds that contain an ethyl group at C-9, with larger C-9 substituents tending to decrease D1R affinity. A number of novel ligands were identified, such as compounds 12a and 12b, with nanomolar affinities for D1R and no affinity for either D2R or D3R, with compound 12a being identified as a D1R antagonist for both G-protein- and β-arrestin-based signaling. Compound 23b was identified as the most potent and selective D3R ligand containing a THPB template to date and functions as an antagonist for both G-protein- and β-arrestin-based signaling. Molecular docking and molecular dynamics studies validated the D1R and D3R affinity and selectivity of 12a, 12b, and 23b.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z