Abstract
We have utilized multiparametric surface plasmon resonance and impendance-based quartz crystal microbalance instruments to study the distribution coefficients of catechol derivatives in cell model membranes. Our findings verify that the octanol–water partitioning coefficient is a poor descriptor of the total lipid affinity for small molecules which show limited lipophilicity in the octanol–water system. Notably, 3-methoxytyramine, the methylated derivative of the neurotransmitter dopamine, showed substantial affinity to the lipids despite its nonlipophilic nature predicted by octanol–water partitioning. The average ratio of distribution coefficients between 3-methoxytyramine and dopamine was 8.0. We also found that the interactions between the catechols and the membranes modeling the cell membrane outer leaflet are very weak, suggesting a mechanism other than the membrane-mediated mechanism of action for the neurotransmitters at the postsynaptic site. The average distribution coefficient for these membranes was one-third of the average value for pure phosphatidylcholine membranes, calculated using all compounds. In the context of our previous work, we further theorize that membrane-bound enzymes can utilize membrane headgroup partitioning to find their substrates. This could explain the differences in enzyme affinity between soluble and membrane-bound isoforms of catechol-O-methyltransferase, an essential enzyme in catechol metabolism.
Highlights
Octanol−water partition coefficient for an un-ionized compound is a descriptor for the ability of small molecular drugs to passively permeate through the cellular membranes of the body.[1,2] It belongs to the Lipinski’s rule of five parameters which describe the drug-likeness of a molecule.[3]
We have recently suggested that the membrane-bound isoform of catechol-O-methyltransferase (MB-COMT) is an interfacial enzyme.[12]
The conventional surface plasmon resonance technique records the change in the SPR peak minimum angle, referred to as the “SPR response”
Summary
Octanol−water partition coefficient for an un-ionized compound (log Poct/w) is a descriptor for the ability of small molecular drugs to passively permeate through the cellular membranes of the body.[1,2] It belongs to the Lipinski’s rule of five parameters which describe the drug-likeness of a molecule.[3] Ghose et al have later suggested a qualifying range of −0.4 to 5.6 for log Poct/w, and since the importance of pH-dependent dissociation in the prediction of drug behavior in the body compartments has been acknowledged.[4,5] While the pH-dependent counterpart of the partition coefficient, distribution coefficient (log Doct/w), should be used instead of log Poct/w for studying compounds, the correlation between log Poct/w or log Doct/w and lipid membrane partitioning is sometimes assumed.[6] electrostatic interactions and the capability for compounds to form hydrogen bonds with the lipid headgroups at the membranewater interface are not taken into account by the octanol− water partitioning coefficients.[7] In a more rigorous treatment of the analyte binding, two partition coefficients should be described, one for the aqueous-interfacial binding and another for the partitioning from the interface to the bilayer interior.[8,9]
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