Unraveling the Structural Basis of P-glycoprotein Transport of Serotonin 5-HT1B/1D Receptor Agonists: Eletriptan and Sumatriptan

P-glycoprotein (Pgp) acts as the gatekeeper at the blood-brain barrier by preventing the entry of toxic insults; however, drugs that are Pgp substrates cannot penetrate the blood-brain barrier to treat central nervous system (CNS) disorders and diseases. Serotonin 5-HT1B/1D receptor agonists are members of the triptan class of drugs that abort migraines during the onset of symptoms and are known Pgp substrates. While members of a drug class are structurally similar, eletriptan (Relpax®, ETT) and sumatriptan (Imitrex®, STT) have large differences in their Pgp efflux ratios. To understand the relationship between drug binding and efflux, ETT and STT were used to probe the structural basis of triptan transport. From ATPase activity assays, ETT stimulated Pgp ATP hydrolysis and was fit to the Michaelis-Menten equation. In contrast, STT induced very little activation of the Pgp-coupled hydrolysis. Protein fluorescence quenching was used to determine the binding affinities and the number of binding sites of ETT...