Cholesterol and Lipid Phases Influence the Interactions between Serotonin Receptor Agonists and Lipid Bilayers

Abstract

Solid state NMR techniques have been used to investigate the effect that two serotonin receptor 1a agonists (quipazine and LY-165,163) have on the phase behavior of, and interactions within, cholesterol/phosphocholine lipid bilayers. The presence of agonist, and particularly LY-165,163, appears to widen the phase transitions, an effect that is much more pronounced in the presence of cholesterol. It was found that both agonists locate close to the cholesterol, and their interactions with the lipids are modulated by the lipid phases. As the membrane condenses into mixed liquid-ordered/disordered phases, quipazine is pushed up toward the surface of the bilayer, whereas LY-165,163 moves deeper into the lipid chain region. In light of our results, we discuss the role of lipid/drug interactions on drug efficacy.The majority of drug targets are membrane proteins. Hence the interaction of a drug with the membrane is crucial for its efficacy. A high location probability in a particular part of a membrane and its orientation with respect to the membrane normal could well be relevant to how the drug is presented to the target protein's binding site (1, 2). Cholesterol-rich microdomains ("lipid rafts") add another layer of complexity because the lateral organization of the membrane could well affect the concentration of a drug close to its target protein. This possibility is backed up by the observation that many chemicals, including drugs that target serotonin receptors, preferentially localize into these domains (3-5). Meanwhile, the location and activity of some membrane proteins, particularly G-protein-coupled receptors, seem to be affected by domains (6). Therefore, it is easy to imagine that a drug's efficacy may be limited by it partitioning into a different membrane domain than its target receptor. Furthermore, it is clear that many membrane proteins are modulated by the properties of the surrounding lipids. Hence, a drug has the potential to regulate a protein by altering these properties (7). This raises the intriguing possibility of a class of drugs that, instead of directly targeting a protein, target the membrane in which the protein resides. This route of action was first proposed as early as 1899 as a possible mechanism for general anesthetics, when it was noted that the potency of an anesthetic correlated very strongly with olive oil/water partitioning (8), yet drugs affecting membrane proteins via lipid interactions, so called "membrane-lipid therapy," have only relatively recently been explored (7, 9, 10).Some simple lipid mixtures have been used as models for in vivo microdomains. A particularly well studied mixture consists of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) Proton NMR and specifically magic angle spinning-assisted nuclear Overhauser enhancement spectroscopy (MAS-NOESY) experiments have proven to be an excellent tool for investigating, with atomic resolution, the location of small molecules embedded in lipid membranes (17)(18)(19)(20). However, these studies have been limited to binary...

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Cellular Membrane Phospholipids Act as a Depository for Quaternary Amine Containing Drugs thus Competing with the Acetylcholine/Nicotinic Receptor

“…2 Determination of protein−protein, protein−drug, 3−5 or lipid−drug 6−11 interactions are important for ADMET (absorption, distribution, metabolism, elimination, and toxicology) in preclinical studies. Lipid−drug molecular interactions have been widely studied by fluorescence, 3 NMR, 12,13 and surface plasmon resonance. 14,15 The neuronal nicotinic acetylcholine receptor (nAChR) consists of five subunits (e.g., α, β, γ, and δ) and has been well characterized.…”

“…Determination of protein–protein, protein–drug, − or lipid–drug − interactions are important for ADMET (absorption, distribution, metabolism, elimination, and toxicology) in preclinical studies. Lipid–drug molecular interactions have been widely studied by fluorescence, NMR, , and surface plasmon resonance. , …”