Armodafinil’in membran lipidleri etkileşiminin DPPC model membran sistemi ile araştırılması

Öz

Amaç: Modafinilin rasemik bileşiğinin R-enantiyomeri olan Armodafinil ARM tam olarak bilinmeyen hücresel etki mekanizması ile uyku bozukluklarında kullanılan merkezi sinir sistemi MSS uyarıcı ve uyanıklığı arttırıcı bir ajandır. Her ne kadar ARM’nin uyku/uyanıklık düzenini etkileyen enzimlere ve reseptörlere bağlanmadığı ve vücutta çok iyi dağıldığı gösterilse de, bildiğimiz kadarıyla onun MSS’deki etkinliğini değerlendiren bir çalışma bulunmamaktadır. Bir ilacın lipid çözünürlüğünün onun MSS erişilebilirliğini direkt olarak etkilediği göz önünde bulundurulduğunda ARM’nin lipidlerin içine nasıl nüfuz ettiği ve onlarla ne tarz etkileşmelere girdiğinin araştırılması bu konuya faydalı katkılar sağlayabilir. Bu bağlamda, bu çalışmada dipalmitoilfosfatidilkolin DPPC multilamellar veziküler MLVs adlı basitleştirilmiş model membran sistemi ile ARM’in konsantrasyona bağlı etkileşmeleri araştırıldı.Yöntem: ARM’nin DPPC MLV’lerinin ana geçiş sıcaklığı Tm , entalpi ΔH , kooperatiflik birimi CU ve CH2 asimetrik, C = O simetrik ve PO2- asimetrik frekans değerleri üzerine etkileri konsantrasyona bağlı % 1-1020 mol olarak diferansiyel tarama kalorimetresi DSC ve fourier dönüşümü infrared FT-IR spektroskopisi kullanılarak incelendi. Results: All data showed that with the addition of ARM at all concentrations into pure DPPC MLVs, decreased lipid order acyl chain flexibility , but increased lipid dynamics fluidity , glycerol backbone and hydrogen bonding capacity head groups of lipids in the gel and liquid crystalline phases. Moreover, it also caused to shift Tm, ΔH and CU to lower values. Conclusion: The corresponding findings revealed that ARM has high affinity for binding to acyl chains and hydrophilic parts of phosphatidylcholine lipids. This was also supported by the obtained differences in the thermotropic properties of lipids caused by ARM. The high tendency of ARM to interact with lipids may also mean that it may also lead to perturb the packing of membrane lipids. The results provides incorporation profile of ARM into biological membranes depending on concentration, which may further contribute to new drug development against sleep disorders and related diseases. Bulgular: Elde edilen tüm verilere göre saf DPPC MLV’lerine ARM eklenmesiyle, lipit düzeninde açil zincir esnekliği azalmaya karşılık lipid dinamiği akışkanlık , gliserol omurgası ve lipid kafa gruplarının hidrojen bağlama kapasitelerinde sıvı ve kristal fazda artma olduğu tespit edildi. Ayrıca, Tm, ΔH ve CU parametrelerinin de daha düşük değerlere kaydığı bulundu.Sonuç: Tüm bulgular, ARM’nin, fosfatidilkolin lipidlerinin açil zincirlerine ve hidrofilik kısımlarına bağlanmak üzere yüksek afinite gösterdiğini ortaya koydu. Bu durum ARM’nin lipidlerin termotrofik parametrelerinde neden olduğu farklılıklarla da desteklendi. ARM’nin lipidlerle yüksek oranda etkileşime girme eğilimi onun membran lipidlerinin paketlenmesini bozmasına da neden olabileceği anlamına gelebilir. Elde edilen tüm sonuçlar ARM’nin biyolojik membranlar ile ne tarz etkileşmelere girdiği ile ilgili bilgiler sunmakla birlikte uyku düzensizlikleri ve ilgili hastalıklara karşı yeni ilaç geliştirme çalışmalarına katkı sağlayabilir

Anahtar Kelimeler

• Darmodafinil,FT-IR, DSC, ilaçlipid etkileşmeleri, dipalmitoilfosfatidilkolin

The investigation of the interaction of Armodafinil with membrane lipids by using DPPC model membrane system

Öz

Objective: Armodafinil ARM , the R-enantiomer of the racemic compound of modafinil, is a central nervous system CNS stimulant and wakefulness-promoting used in sleep disorders with unknown exact cellular mechanism. Although it was shown that it does not binds to enzymes and receptors that regulate sleep/wake regulation as well as it is very-well distributed in the body, there is no report evaluating its CNS availability to the best of our knowledge. Considering that lipid solubility of a drug directly affects CNS accessibility, the investigation of ARM how to penetrate into and to interact with lipids would be beneficial to contribute to such issue. Related with this, the interaction of ARM with simplified model membrane system named dipalmitoylphosphatidylcholine DPPC multilamellar vesicles MLVs depending on concentrations was investigated in the present study.Methods: The effects of ARM as a function of concentration 1-10-20 mol % on main transition temperature Tm , enthalpy ΔH , cooperativity unit CU and frequency values of CH2 asymmetric, C=O symmetric and PO2- asymmetric stretching of DPPC MLVs were studied by utilizing differential scanning calorimetry DSC and fourier transform infrared FT-IR spectroscopy

Anahtar Kelimeler

• Darmodafinil, FT-IR spectroscopy, DSC, drug-lipid interaction, dipalmitoylphosphatidylcholines

Kaynakça

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