Intramolecular hydrogen bonding in articaine can be related to superior bone tissue penetration: a molecular dynamics study |
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Authors: | Skjevik Age Aleksander Haug Bengt Erik Lygre Henning Teigen Knut |
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Affiliation: | a Department of Biomedicine, University of Bergen, N-5009 Bergen, Norwayb Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norwayc Centre for Pharmacy, Department of Chemistry, University of Bergen, N-5007 Bergen, Norwayd Section of Pharmacology, Institute of Medicine, University of Bergen, N-5020 Bergen, Norway |
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Abstract: | Local anesthetics (LAs) are drugs that cause reversible loss of nociception during surgical procedures. Articaine is a commonly used LA in dentistry that has proven to be exceptionally effective in penetrating bone tissue and induce anesthesia on posterior teeth in maxilla and mandibula. In the present study, our aim was to gain a deeper understanding of the penetration of articaine through biological membranes by studying the interactions of articaine with a phospholipid membrane. Our approach involves Langmuir monolayer experiments combined with molecular dynamics simulations. Membrane permeability of LAs can be modulated by pH due to a titratable amine group with a pKa value close to physiological pH. A change in protonation state is thus known to act as a lipophilicity switch in LAs. Our study shows that articaine has an additional unique lipophilicity switch in its ability to form an intramolecular hydrogen bond. We suggest this intramolecular hydrogen bond as a novel and additional solvent-dependent mechanism for modulation of lipophilicity of articaine which may enhance its diffusion through membranes and connective tissue. |
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Keywords: | CM, center of mass DMPC, dimyristoyl-phosphatidylcholine GAFF, general amber force field IANB, inferior alveolar nerve block LA, local anesthetic MD, molecular dynamics NMR, nuclear magnetic resonance NPT, constant number of particles (N), pressure (P) and temperature (T) NVT, constant number of particles (N), volume (V) and temperature (T) POPC, palmitoyl-oleoyl-phosphatidylcholine (R)-A, neutral state of (R)-articaine (R)-AH+, protonated state of (R)-articaine (S)-A, neutral state of (S)-articaine RESP, restrained electrostatic potential RMSd, root mean square deviation |
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