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

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.

Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function

“…Cloned human 5-HT 1A and 5-HT 2A receptors were stably expressed in HEK293 cells and grown under constant selective pressure using 100 μg/mL G418 as previously described (Chang et al, 2009; Cummings et al, 2010). …”

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz

“…The 5-HT 2A receptor density was then estimated using 0.5 nM [ 3 H]MSP followed by the calculation of B max at saturation using a rectangular hyperbola model B max = (Y •(K D +X))/X, where Y is [specific binding] and X = [radioligand concentration]. The K D for [ 3 H]MSP at the cloned human 5-HT 2A receptor had been previously determined to be 246 pM [25]. The protein concentration for each sample was determined using the BCA assays as described in section 2.8.…”

Synthesis and antifungal activity of novel streptochlorin analogues

“…The synthetic routes to the streptochlorin analogues are shown in Scheme 2, and the indole substituents are shown in Scheme 3. The required substituted indole-3-carboxaldehydes 4 were either commercially available, or could be made by Vilsmeier-Haack formylation of the corresponding substituted indoles 3 [16,17]. The indole nitrogen was then sulfonylated to give the protected indole-3-carboxaldehydes 5.…”