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

Abstract

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 CH₂group 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 (L(β)') but destabilizes the ripple phase (P(β)'). These observations provide a thermodynamic basis for understanding the functional role of NASTs in their parent tissues.

Self-assembly, supramolecular organization, and phase transitions of a homologous series of N-acyl-l-alanines (n=8–20)

“…However, this type of odd-even alteration was observed earlier with phosphatidylcholines bearing -tertiary-butyl fatty acyl chains and phosphatidylcholines containing dl-methyl anteisobranched fatty acyl chains in the hydrated state [34,35]. The enthalpy and entropy data for NAAs of even and odd acyl chain lengths could be fit well to expressions (2) and (3) [29] given below as observed previously with N-acylethanolamines, Nacyldopamines, and N-acylserotonins with even and odd acyl chain lengths, O-acylcholines with even chain lengths as well as N-,Odiacylethanolamines with matched as well as mixed acyl chains [31][32][33][36][37][38][39].…”

“…However, when the data obtained with even-and oddchain length series are viewed together, a zig-zag pattern is seen with the values of enthalpy and entropy for the odd-chain length series being slightly higher than those of even-chain length series, i.e., the calorimetric data exhibit odd-even alteration. This observation is rather unusual since for many other homologous series such as long chain fatty acids, hydrocarbons, alcohols, N-acylethanolamines, N-acyldopamines, N-acylserotonins, and N-,O-diacylethanolamines the values of thermodynamic parameters for the odd chain length series are lower as compared to those of the even chain length series [29][30][31][32][33]. However, this type of odd-even alteration was observed earlier with phosphatidylcholines bearing -tertiary-butyl fatty acyl chains and phosphatidylcholines containing dl-methyl anteisobranched fatty acyl chains in the hydrated state [34,35].…”

Characterization of βN-Octadecanoyl-5-hydroxytryptamide Anti-Inflammatory Effect

“…C 18 -5HT was synthesized using an adapted protocol by Reddy and Swamy [ 10 ]. The NRM spectra, melting point, and exact mass of the pure product are per the literature [ 10 , 11 ].…”

“…C 18 -5HT was synthesized using a condensation reaction between stearic acid and serotonin, which was adapted from Reddy and Swamy [ 10 ]. Stearic acid (1.1 eq), DMAP (1.0 eq), serotonin hydrochloride (1.0 eq.…”

Two New βN-Alkanoyl-5-Hydroxytryptamides with Relevant Antinociceptive Activity

“…The strategies that have been reported so far for the synthesis of C n -5HT have several limitations, such as low yield, two or three consecutive and laborious steps, and the use of toxic reagents and high-boiling solvents, hence, the need for a new synthetic strategy to produce these molecules is urgent [ 14 , 15 ]. Mechanochemistry is a powerful tool for molecular synthesis, in which the energy required for the reaction to occur is induced by the absorption of mechanical energy from the shock between the spheres in a ball mill.…”