The rate of entry of drugs into brain is thought to be a factor in their abuse liability. In this... more The rate of entry of drugs into brain is thought to be a factor in their abuse liability. In this investigation, we have examined the rate of entry and binding at dopamine transporters in mouse striatum for a variety of dopamine transporter inhibitors. The method utilized was based on measuring the displacement of3H-WIN 35,428 from striatal dopamine transporter sites in vivo at different times. Eleven cocaine analogs (RTI-31, RTI-32, RTI-51, RTI-55, RTI-113, RTI-114, RTI-117, RTI-120, RTI-121, WIN 35,065-2, and WIN 35,428) as well as other dopamine uptake site blockers (bupropion, nomifensine, and methylphenidate) were compared with (−) cocaine for their rates of displacement of3H-WIN 35,428 binding in vivo. The drugs that displayed the fastest occupancy rates were bupropion, (−) cocaine, nomifensine, and methylphenidate. RTI-51, RTI-121, RTI-114, RTI-117, RTI-120, RTI-32, RTI-55, and RTI-113, showed intermediate rates, whereas RTI-31, WIN 35,065-2, and WIN 35,428 exhibited the slowest rates of displacement. While many of the cocaine analogs have proven to be behaviorally and pharmacologically more potent than (−) cocaine, their rates of entry and binding site occupancy were slower than that for (−) cocaine. Earliest times of transporter occupancy by the different drugs were correlated (although weakly) with their degree of lipophilicity (r=0.59;P<0.02). Kinetic effects and metabolism of the compounds could complicate the interpretations of these data. There was no obvious correlation between rate of occupancy in this animal model and abuse liability in humans, which is consistent with the notion that other factors are critical as well.
We have purified proteins of 70 kD from Drosophila, HeLa cells, and Z. mays that specifically bin... more We have purified proteins of 70 kD from Drosophila, HeLa cells, and Z. mays that specifically bind nuclear localization sequences (NLSs). These proteins are recognized by antibodies raised against a previously identified NLS-binding protein (NBP) from the yeast S. cerevisiae. All NBPs are associated with nuclei and also present in the cytosol . NBPs are phosphorylated and phosphatase treatment abolished NLS binding . The requirement for NBPs in nuclear protein uptake is demonstrated in semipermeabilized Drosophila melanogaster tissue culture cells . Proper import of T HE composition of the nucleus requires vectorial transport of macromolecules across the nuclear envelope. Thus far, import of proteins into the nucleus could be divided into several steps . The initial reaction includes specific recognition and binding of nuclear proteins at the nuclear envelope . This is followed by ATP-and temperaturedependent translocation through the nuclear pore complex .
The rate of entry of drugs into brain is thought to be a factor in their abuse liability. In this... more The rate of entry of drugs into brain is thought to be a factor in their abuse liability. In this investigation, we have examined the rate of entry and binding at dopamine transporters in mouse striatum for a variety of dopamine transporter inhibitors. The method utilized was based on measuring the displacement of3H-WIN 35,428 from striatal dopamine transporter sites in vivo at different times. Eleven cocaine analogs (RTI-31, RTI-32, RTI-51, RTI-55, RTI-113, RTI-114, RTI-117, RTI-120, RTI-121, WIN 35,065-2, and WIN 35,428) as well as other dopamine uptake site blockers (bupropion, nomifensine, and methylphenidate) were compared with (−) cocaine for their rates of displacement of3H-WIN 35,428 binding in vivo. The drugs that displayed the fastest occupancy rates were bupropion, (−) cocaine, nomifensine, and methylphenidate. RTI-51, RTI-121, RTI-114, RTI-117, RTI-120, RTI-32, RTI-55, and RTI-113, showed intermediate rates, whereas RTI-31, WIN 35,065-2, and WIN 35,428 exhibited the slowest rates of displacement. While many of the cocaine analogs have proven to be behaviorally and pharmacologically more potent than (−) cocaine, their rates of entry and binding site occupancy were slower than that for (−) cocaine. Earliest times of transporter occupancy by the different drugs were correlated (although weakly) with their degree of lipophilicity (r=0.59;P<0.02). Kinetic effects and metabolism of the compounds could complicate the interpretations of these data. There was no obvious correlation between rate of occupancy in this animal model and abuse liability in humans, which is consistent with the notion that other factors are critical as well.
We have purified proteins of 70 kD from Drosophila, HeLa cells, and Z. mays that specifically bin... more We have purified proteins of 70 kD from Drosophila, HeLa cells, and Z. mays that specifically bind nuclear localization sequences (NLSs). These proteins are recognized by antibodies raised against a previously identified NLS-binding protein (NBP) from the yeast S. cerevisiae. All NBPs are associated with nuclei and also present in the cytosol . NBPs are phosphorylated and phosphatase treatment abolished NLS binding . The requirement for NBPs in nuclear protein uptake is demonstrated in semipermeabilized Drosophila melanogaster tissue culture cells . Proper import of T HE composition of the nucleus requires vectorial transport of macromolecules across the nuclear envelope. Thus far, import of proteins into the nucleus could be divided into several steps . The initial reaction includes specific recognition and binding of nuclear proteins at the nuclear envelope . This is followed by ATP-and temperaturedependent translocation through the nuclear pore complex .
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Papers by Ursula Bustos