A sumatriptan coarse-grained model to explore different environments: interplay with experimental techniques.

In this work, we developed a coarse-grained model of sumatriptan suitable for extensive molecular dynamics simulations. First, we confirmed the interfacial distribution of this drug in bilayers through cryogenic transmission electron microscopy and small-angle X-ray scattering techniques, as was predicted by our previous atomistic simulations. Based on these simulations, we developed a coarse-grained model for sumatriptan able to reproduce its overall molecular behavior, captured by atomistic simulations and experiments. We then tested the sumatriptan model in a micellar environment along with experimental characterization of sumatriptan-loaded micelles. The simulation results showed good agreement with photon correlation spectroscopy and electrophoretic mobility experiments performed in this work. The particle size of the obtained micelles was comparable with the simulated ones; meanwhile, zeta-potential results suggest adsorption of the drug on the micellar surface. This model is a step forward in the search for a suitable drug-delivery system for sumatriptan.

Triptan partition in model membranes.

In this work, we report a molecular dynamics simulations study of protonated triptans, sumatriptan and naratriptan, in a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline (POPC). The simulations were carried out at two concentrations for each drug. Our results show partition between the lipid head-water interphase and water phase for both triptans, with increasing access to the water phase with increasing concentrations. The triptans were stabilized at the interphase through different specific interactions with the POPC bilayer such as hydrogen bonds, salt bridges, and cation-π. Besides, sumatriptan and naratriptan protonated molecules have no access to the hydrophobic region of the bilayer at the studied conditions. Similar results were found for both drugs, however protonated naratriptan shows slightly higher affinity for the water phase. This behavior was attributed to the bulky lateral amino group in its structure under the studied conditions (drugs were originally placed at the water phase). This work represents a first insight to the comprehensive understanding of triptan partition in model membranes.

Triptan drugs, natural killer cell cytotoxicity, and neutrophils pro-matrix metalloproteinase-9 secretion.

OBJECTIVE: To study the effect of various triptan-like drugs, eg, avitriptan, naratriptan, and sumatriptan, as well as the benzopyran alnitidan, on the natural killer cell (NKC) activity of peripheral blood mononuclear cell (PBMC) samples and highly purified NKC (HPNKC) preparations. We also examined the possible role of these agents as immunomodulators by studying their effect upon the in vitro secretion of pro-matrix metalloproteinase-9 (pMMP-9) from whole blood and purified neutrophils samples. BACKGROUND: The pharmacological profile of a large number of triptan-like compounds has been extensively studied. However, relatively little is known of their interactions with cellular components of the immune system. METHODS: Blood was obtained from nonsmoking, drug-free healthy individuals from the Blood Bank of the University of Chile main Clinical Hospital (J.J.A.). PBMC were separated by centrifugation and HPNKC acquired by an immunomagnetic isolation procedure. NKC cytotoxicity was assayed using (51)Cr-labeled K-562 cells as target. Addition of drugs and of effector cells (30 : 1, 50 : 1, and 70 : 1 ratio for PBMCs, and 5 : 1 for HPNKCs) was followed by incubation. Paired Student's t-test (2-tailed) was used to determine the significance of the specific (51)Cr release in controls vs drug-treated samples. Aliquots of whole blood or purified neutrophils were added test drug, incubated, centrifuged, and the supernatant analyzed by gelatine zymography. Gelatinolytic activity was visualized, and a digested zone at MW 92 kD indicated presence of pMMP-9. Area of proteolysis was estimated by densitometry; prestained standards were used to assess pMMP-9 molecular weight. RESULTS: Peripheral blood mononuclear cell's NKC cytotoxicity was consistently decreased after incubation with each and every one of the drugs tested. This result, observed for the 3 effector : target (E : T) cell ratios used, was relatively similar among the various compounds studied, and reached statistical significance only at E : T 70 : 1. Similar drug treatment failed, however, to produce significant changes in the cytotoxicity of HPNKC preparations, suggesting that modulation of the PBMC's NKC activity and that of HPNKC samples require different kinds of cell's derived signal. Incubation with either of the drugs tested failed to significantly alter (basal) nonstimulated pMPP-9 secretion by whole blood samples. However, basal pMMP-9 secretion by purified neutrophil preparations was significantly inhibited by alnitidan and sumatriptan, and not affected by naratriptan. CONCLUSIONS: Various drugs with a triptan-like chemical structure interact with cellular components of the innate immune system, resulting in an apparent indirect inhibition of NKC activity and direct inhibition of neutrophils pMMP-9 secretion. These results suggest that they may play a positive role in decreasing the severity of inflammatory processes. Whether this effect is part of triptans antimigraine mechanism of action, or just an added beneficial effect of their use for the reversal treatment of migraine headaches remains to be explored.