First synthesis of thiazepino[3,4‐a]isoquinolines, a facile new synthetic route to diazepino[3,4‐a]isoquinolines and assessment of their dopamine and σ receptor affinities

Cordone, Pierpaolo; Krishna, Namballa Hari; Harding, Wayne W.

doi:10.1002/jhet.4086

Cited by 3 publications

(1 citation statement)

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“…Our lab has a continuing interest in optimizing THPBs as selective D1R and selective D3R targeted agents, as these may be valuable pharmacological tools and experimental therapeutics for a variety of CNS disorders, including cocaine abuse. − We are also interested in obtaining compounds with potent and selective dual D1R/D3R targeting properties . Our premise here is that compounds with a D1R agonist/D3R antagonist profile may be novel, effective anti-cocaine therapeutics, given that (i) the known anti-cocaine effects of both D1R agonists , and D3R antagonists , and (ii) our previous study in which the combination of the D1R partial agonist SKF 77434 and the D3R antagonist NGB 29104 robustly decreased cocaine seeking and reward in rats …”

Section: Introductionmentioning

confidence: 99%

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

Namballa,

Dorogan,

Gudipally

et al. 2023

J. Med. Chem.

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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.

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