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Tetrahydroprotoberberine alkaloids with dopamine and σ receptor affinity.

Abstract：

:Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n-alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues (10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity. De-rigidification of stepholidine resulted in decreased affinity at all receptors evaluated; thus the tetracyclic THPB framework is advantageous for affinity at dopamine and σ receptors. Docking of the C10 analogues at the D3 receptor, suggest that an ionic interaction between the protonated nitrogen atom and Asp110, a H-bond interaction between the C2 phenol and Ser192, a H-bond interaction between the C10 phenol and Cys181 as well as hydrophobic interactions of the aryl rings to Phe106 and Phe345, are critical for high affinity of the compounds.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Gadhiya S,Madapa S,Kurtzman T,Alberts IL,Ramsey S,Pillarsetty NK,Kalidindi T,Harding WW

doi

10.1016/j.bmc.2016.03.037

subject

Has Abstract

pub_date

2016-05-01 00:00:00

pages

2060-71

issue

9

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)30193-6

journal_volume

24

pub_type

杂志文章

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