Structural and dynamical evidences of triptan interaction in model membranes combining simulations and NMR

IRENE WOOD; KATIA SEREMETA; LUCAS FABIAN; DANIELE RIBEIRO DE ARAUJO; LUIS FERNANDO CABECA; ENEIDA DE PAULA; MONICA PICKHOLZ

Puerto Iguazu, Misiones

Conferencia; 56th International Conference on the Bioscience of lipids; 2015

Triptans were designed based on serotonin structure to be used as antimigraine drugs . The action mechanism of triptans is under discussion. It was hypothesized that drug penetration in the central nervous system -through the blood-brain barrier- could be associated with triptan pharmacological efficacy and safety . In order to obtain a comprehensive understanding and comparison of triptans partition and permeation in lipid bilayer, we report a physico-chemical study of sumatriptan and naratriptan in phosphatidyl-choline model membranes. Molecular dynamics simulations were carried out from different initial conditions and for different drug ionization forms. Our results show that triptans partition and interactions depend both on environment and ionization state. As a general trend, protonated sumatriptan and naratriptan have no access to the hydrophobic region of the bilayer from the water phase. Bearing an indolic moiety, both drugs show preference for lipid headgroups-water interphase. Dynamic information was also obtained by nuclear magnetic resonance (1H-NMR). Main effects were observed at the polar headgroups and upper positions of the acyl-chains. Changes in chemical shifts and longitudinal relaxation times of specifical protons were attributed to drug inmobilization and interaction with lipid membrane. Together, simulation and spectroscopic data strongly suggest an interfacial distribution of both drugs. The difference in behavior between sumatriptan and naratriptan is attributed to steric effects, mainly through the bulky lateral amino group in naratriptan structure.