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Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT2 and ?1 receptor antagonists.

ABSTRACT: In this study, the (S)-enantiomers of the aporphine alkaloids, nuciferine and roemerine, were prepared via a synthetic route involving catalytic asymmetric hydrogenation and both stereoisomers were evaluated in vitro for functional activity at human 5-HT2 and adrenergic ?1 receptor subtypes using a transforming growth factor-? shedding assay. Both enantiomers of each of the compounds were found to act as antagonists at 5-HT2 and ?1 receptors. (R)-roemerine was the most potent compound at 5-HT2A and 5-HT2C receptors (pKb = 7.8-7.9) with good selectivity compared to (S)-roemerine at these two receptors and compared to its activity at 5-HT2B, ?1A, ?1B and ?1D receptors.

SUBMITTER: Heng HL

PROVIDER: S-EPMC6072365 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT2 and α1 receptor antagonists.

Heng Hui Li HL Chee Chin Fei CF Chin Sek Peng SP Ouyang Yifan Y Wang Hao H Buckle Michael J C MJC Herr Deron R DR Paterson Ian C IC Doughty Stephen W SW Abd Rahman Noorsaadah N Chung Lip Yong LY

MedChemComm 20180226 3

In this study, the (S)-enantiomers of the aporphine alkaloids, nuciferine and roemerine, were prepared via a synthetic route involving catalytic asymmetric hydrogenation and both stereoisomers were evaluated in vitro for functional activity at human 5-HT2 and adrenergic α1 receptor subtypes using a transforming growth factor-α shedding assay. Both enantiomers of each of the compounds were found to act as antagonists at 5-HT2 and α1 ...[more]

PMID: 30108948

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Project description:As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11?-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11?-(substituted aryl) estradiol analogs were potent antagonists of the ER. Little information existed about the specific structural features involved in the transition from agonism to antagonism for the 11?-aryl estradiol analogs or their potential as scaffolds for drug conjugation.We prepared and characterized a series of 11?-(4-Substituted phenyl) estradiol analogs using modifications of existing synthetic methods. The new compounds, as well as standard steroidal agonists and antagonists, were evaluated as competitive ligands for the ER?-LBD. Functional assays used the induction of alkaline phosphatase in Ishikawa cells to determine potency of the compounds as ER agonists or antagonists.The synthetic strategy successfully generated a series of compounds in which the 4-substituent was sequentially modified from hydroxyl to methoxy to azidoethoxy/N,N-dimethylaminoethoxy and eventually to a prototypical 1,4-naphthoquinone-containing moiety. The new compounds all retained high relative binding affinity (RBA) for the ER?-LBD, ranging from 13-83% that of estradiol. No subtype selectivity was observed. More importantly, the transition from agonist to antagonist activity occurs at the 4-methoxy stage where the compound is a mixed antagonist. More notably, antagonism appeared to be more dependent upon the size of the 11?-substituent than upon the nature of the terminal groupWe have developed a synthetic strategy that provides facile access to potent 11?-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ER?-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11?-phenyl ring had little additional effect on either affinity or efficacy, suggesting the incorporation of diverse imaging or biologically active groups can be attached without significantly compromising the ER-binding capacity. Future studies are in progress to exploit the 11?-aryl estradiol analogs as potential drug delivery systems and imaging agents.

Dataset Information

Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT2 and ?1 receptor antagonists.

Publications

Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT<sub>2</sub> and α<sub>1</sub> receptor antagonists.

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