STRUCTURAL AND DYNAMICAL EVIDENCES OF TRIPTAN PARTITION AND INTERACTION IN MODEL MEMBRANES

I. WOOD; K. SEREMETA; D. ARAUJO; L. F. CABECA; E. DE PAULA; M. PICKHOLZ

IGUAZU

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

ICBL

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 the drug penetration in the central nervous system -through the blood-brain barrier- could be associated with triptan phamacological 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 depends 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. Simulation and spectroscopic data together strongly suggest an interphacial 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. Keywords: Triptans; Membrane; Nuclear Magnetic Resonance, Molecular DynamicsAcknowledgements: ANPCyT, UBA, CONICET