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. 2010 Jul 1;18(13):4783-92.
doi: 10.1016/j.bmc.2010.05.017. Epub 2010 May 15.

Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

David F Cummings  1 , Diana C Canseco, Pratikkumar Sheth, James E Johnson, John A Schetz
Affiliations

Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

David F Cummings et al. Bioorg Med Chem. .

Abstract

Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure-affinity relationships of derivatives based on the aplysinopsin natural product pharmacophore. Twenty aplysinopsin derivatives were synthesized, purified and tested for their affinities for cloned human serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptor subtypes. Four compounds in this series had >30-fold selectivity for 5-HT2A or 5-HT2C receptors. The compound (E)-5-((5,6-dichloro-1H-indol-3-yl)methylene)-2-imino-1,3-dimethylimidazolidin-4-one (UNT-TWU-22, 16) had approximately 2100-fold selectivity for the serotonin 5-HT2C receptor subtype: an affinity for 5-HT2C equal to 46 nM and no detectable affinity for the 5-HT1A or 5-HT2A receptor subtypes. The two most important factors controlling 5-HT2A or 5-HT2C receptor subtype selectivity were the combined R1,R3-alkylation of the imidazolidinone ring and the type and number of halogens on the indole ring of the aplysinopsin pharmacophore.

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Figures

Figure 1
Figure 1
A) Aplysinopsin pharmacophore and numbering. The original aplysinopsin reported had R1 = R3 = CH3, R2 = R4 = R5 = H. B) The structure of 6-bromo-2′-de-N-methylaplysinopsin or 6-bromo-R3-methylaplysinopsin reported by Hu (also known as Natural Product #6 in that report).
Figure 2
Figure 2
Synthesis of 2-imino-1,3-dimethylimidazolidin-4-one and 3-ethyl-2-imino-1-methylimidazolidin-4-one moieties and subsequent synthesis of aplysinopsin analogs.
Figure 3
Figure 3
Competition binding for selected compounds for cloned serotonin 5-HT2A (open circles) and 5-HT2C (closed circles) receptors (n = 3).
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