Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [125I]RTI-55 in membranes prepared from human, monkey and guinea pig caudate

Rothman, Richard B.; Silverthorn, M L; Glowa, John R.; Matecka, Dorota; Rice, Kenner C.; Carroll, F. Ivy; Partilla, John S.; Uhl, George R.; Vandenbergh, David J.; Dersch, Christina M.

doi:10.1002/(sici)1098-2396(199804)28:4<322::aid-syn8>3.0.co;2-b

Cited by 31 publications

(24 citation statements)

References 66 publications

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“…In addition, cocaine analogues label a novel binding site in rat membranes which is not associated with the classic dopamine, serotonin or noradrenalin transporters (Rothman et al 1995). The functional significance of this DAT site2 is not known.…”

Section: Dopamine Transporter In Vitro Bindingmentioning

confidence: 99%

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

Bergström¹,

Tupala²,

Tiihonen³

2001

Pharmacology & Toxicology

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Much research interest has lately been focused on the dopamine transporter function in brain. Recent findings indicate that dopamine reuptake is more like a highly regulated than a constitutive determinant of dopamine clearance. Positron emission tomography (PET) and single-photon emission tomography (SPET) offer unique methods to study dopamine transporter function. Results from in vivo PET and SPET studies correspond well with in vitro studies performed on post mortem human brain tissue. Considering some of the variances between in vitro and in vivo receptor binding phenomena it may be that the role of a compound to alter binding to monoamine uptake sites in vitro does not indicate its potential to affect monoamine transporters after administration in vivo. This discrepancy may be better understood taking into account recent studies indicating the possibility of a rapid regulation of transporter function and surface expression. Furthermore, the dopamine transporter is a fruitful target for CNS drug discovery. Fundamental nature of drug actions in vivo may be studied using demonstrated in vitro and in vivo imaging methods.

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Section: Dopamine Transporter In Vitro Bindingmentioning

confidence: 99%

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

Bergström¹,

Tupala²,

Tiihonen³

2001

Pharmacology & Toxicology

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“…3 H]nisoxetine (American Radiolabeled Chemicals, St. Louis, MO) as described elsewhere (Rothman et al, 1998). Nonspecific binding was measured using 10 M nisoxetine.…”

Section: Methodsmentioning

confidence: 55%

“…For rat brain transporter binding assays, experiments were carried out in 12 ϫ 75-mm polystyrene tubes that were prefilled with 100 l of drug, 100 l of radioligand, and 50 l of a blocker or buffer (Rothman et al, 1998). For assay of the SERT and DAT, the blockers were either 100 nM 4-(2-benzhydryloxy-ethyl)-1-(4-nitro-benzyl)piperidine oxalate to block the DAT or 100 nM citalopram to block SERT.…”

Section: Methodsmentioning

confidence: 99%

“…Data analysis proceeded as described elsewhere (Rothman et al, 1998). IC 50 values were calculated with the MLAB-PC program (Civilized Software, Bethesda, MD) using the two-or three-parameter logistic equation.…”

Section: Methodsmentioning

confidence: 99%

“…SoRI-6238 was synthesized as described (Temple Jr. et al, 1982). The sources of other chemicals are published (Rothman et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

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Studies of the Biogenic Amine Transporters. XI. Identification of a 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) Analog That Allosterically Modulates the Serotonin Transporter

Nightingale¹,

Dersch²,

Boos³

et al. 2005

J Pharmacol Exp Ther

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The serotonin (5-HT) transporter (SERT) is a member of the twelve transmembrane-spanning transporter family that transports 5-HT across cell membranes in a sodium-dependent manner (Amara and Kuhar, 1993;Uhl and Johnson, 1994). SERT, in the central nervous system, is an important target for a wide range of medications used to treat a variety of psychiatric conditions such as anxiety, depression, and obsessive-compulsive disorder (Gorman and Kent, 1999;Zohar and Westenberg, 2000).Drugs that interact with transporters generally interact with this protein in two distinct ways. Reuptake inhibitors bind to transporter proteins but are not transported. These drugs elevate extracellular concentrations of transmitter by blocking transporter-mediated uptake of transmitters from the synapse. Substrate-type releasers bind to transporter proteins and are subsequently transported into the cytoplasm of nerve terminals. Releasers elevate extracellular Article, publication date, and citation information can be found at

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Discovery of novel peptidic dopamine transporter ligands by screening a positional scanning combinatorial hexapeptide library

Rothman

Baumann

Dersch

et al. 1999

Synapse

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The acute reinforcing effects of cocaine are thought by some to result from cocaine binding to the dopamine (DA) transporter, which inhibits DA uptake and increases synaptic DA levels in the mesolimbic system. Other data suggest that neurotransmitters other than DA contribute to cocaine reinforcement and addiction. These considerations illustrate the need to have additional research tools with which to test the "DA hypothesis." One strategy is to identify drugs which bind to the DA transporter (DAT ligands) but which do not inhibit DA uptake as effectively as cocaine. The purpose of the present study was to identify members of a novel structural class of DAT ligands and to characterize their interactions at the DA transporter. A positional scanning hexapeptide D-amino acid library was screened for inhibition of [(125)I]RTI-55 binding to rat caudate DA transporters. Based on the results, 12 peptides were synthesized. All 12 peptides inhibited [(125)I]RTI-55 binding to DA transporters with IC(50) values, which ranged from 1.8 microM to 12 microM. The two most potent peptides (TPI-669-1 and TPI-669-4) were prepared in larger quantities and were characterized further for activity at the DAT and 5-HT transporter. Both peptides inhibited DA and 5-HT uptake and transporter binding with IC(50)/K(i) values in the low micromolar range. In vivo microdialysis studies demonstrated that both peptides increase extracellular DA and 5-HT in the nucleus accumbens of rats. These data demonstrate that peptides can function as inhibitors of biogenic amine transport. Future work will focus on developing more potent and selective peptides. Published 1999 Wiley-Liss, Inc.

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Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [125I]RTI-55 in membranes prepared from human, monkey and guinea pig caudate

Cited by 31 publications

References 66 publications

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

Studies of the Biogenic Amine Transporters. XI. Identification of a 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) Analog That Allosterically Modulates the Serotonin Transporter

Discovery of novel peptidic dopamine transporter ligands by screening a positional scanning combinatorial hexapeptide library

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