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Hiroyoshi Kawada, Zifeng Zhang, Karen A. Blessing, Peter F. Kador; Molecular Parameters Associated With Uptake Of Multi-functional Antioxidants For The Lens, Retina, And Brain. Invest. Ophthalmol. Vis. Sci. 2012;53(14):481.
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Our laboratory has reported the synthesis of multi-functional antioxidant analogs of N,N-dimethylsulfamoyl-4-(2-pyrimidyl)piperazine, which can independently chelate redox-active metals and scavenge reactive oxygen species (ROS). While they readily accumulate in the lens and retina after oral administration, they fail to significantly reach the brain. To increase the ability of these multi-functionals to cross the blood brain barrier (BBB), a new series of analogs retaining the 2-amino-4-hydroxypyrimidine ring system have been synthesized (HK 1-16). Here, the molecular parameters required to target these analogs to the lens, retina, or brain are defined.
Molecular parameters such as log P and Clog P, that are associated with lipophilicity; dipole moment, which implies an electric moment apart from the total net charge on the molecule; kappa shape index, which is associated with steric bulk of the molecule; molar refractivity, which is related to polarizability of the molecule; and hydrophilic volume of the molecule were calculated by MOE. The new descriptor fMF, which is associated with topology, was calculated as described in J. Med. Chem. 1996, 39, 2887-289. All compounds examined were administered to C57BL/6 mice for 14 days by individually incorporating each compound into chow (0.05%). After 14 days of feeding, all mice were perfused with PBS and drug levels in the brain, lens, and retina were quantified by HPLC-ESI-MS.
Significant negative correlations between the accumulation of drugs in the brain and either the kappa shape index, dipole moment, molar refractivity, or hydrophilic volume were observed (linear fit analysis, R2 = 0.66-0.95, P< 0.05). In contrast, significant positive correlations were observed between the lenticular accumulation of drugs and either the kappa shape index or dipole moment (linear fit analysis, R2 = 0.63-0.87, P< 0.05). No significant correlations between any molecular parameter and the uptake of drugs into the neural retina were observed.
Inverse correlations between the uptake of drugs and their molecule parameters related to steric bulk, refractivity, polarity, and hydrophilic volume, were observed in the brain versus the lens. Although the retina is considered an extention of the brain, no correlations between the examined molecular parameters and accumulation of compound into the retina were observed.
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