Synthesis, physicochemical characterization and membrane interactions of a homologous series of N-acylserotonins: Bioactive, endogenous conjugates of serotonin with fatty acids

• N-Acylserotonins (NASTs) are endogenous amphiphilic molecules.
• Dry and hydrated NASTs exhibit odd–even alternation in thermodynamic parameters.
• PXRD and computational studies indicate NASTs adopt an interdigitated bilayer structure.
• Interaction of N-myristoylserotonin stabilizes tilted gel phase of DMPC.

N-Acylserotonins (NASTs), present in the mammalian gastro-intestinal tract and central nervous tissues, exhibit significant biological and pharmacological activities. In the present study, a homologous series of NASTs have been synthesized and characterized. Differential scanning calorimetric studies show that in the dry and hydrated states the transition temperatures, enthalpies, and entropies of NASTs exhibit odd–even alternation. Both odd and even chain length NASTs independently display linear dependence of the transition enthalpies and entropies on the chain length under dry as well as hydrated conditions, suggesting that the molecular packing and intermolecular interactions in each series (odd or even) are likely to be similar for NASTs with different acyl chain lengths in the dry state as well as in the hydrated state. Powder X-ray diffraction studies indicated that the incremental increase in the d-spacing per CH2 group is 1.023 Å, suggesting that the lipid acyl chains are most likely packed in an interdigitated fashion. Results of computational studies are consistent with this and suggest that the acyl chains of the NASTs are tilted with respect to the bilayer normal. Incorporation of N-myristoylserotonin (NMST) into dimyristoylphosphatidylcholine (DMPC) membranes did not significantly affect the phase transition properties at low mole fractions (1–5 mol%), although distinct decrease in the chain-melting transition temperature and increase in the pretransition temperature were observed at higher contents (7.5–30 mol%), suggesting that NMST increases the stability of the tilted gel phase (Lβ′) but destabilizes the ripple phase (Pβ′). These observations provide a thermodynamic basis for understanding the functional role of NASTs in their parent tissues.

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