Transporter ligands

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

Vaughan R.A., Parnas M.L., Gaffaney J.D. et al. Affinity labeling the dopamine transporter ligand binding site. J. Neurosci. Methods. 143 33, 2005. 

Hsin, L.-W., Dersch, C.M., Baumann, M.H. et al. (2002) Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents chiral hydroxyl-containing derivatives of l-[2-[bis (4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and l-[2-(diphenylmethoxy)ethyl]-4-(3-phe-nylpropyl)piperazine. Journal of Medicinal Chemistry, 45 (6), 1321-1329. 

Barker, E. L., Kimmel, H. L., and Blakely, R. D. (1994) Chimeric human and rat serotonin transporters reveal domains involved in recognition of transporter ligands. Mol. Pharmacol. 46, 799-807. 

Vaughan, R. A. and Kuhar, M. J. (1996) Dopamine transporter ligand binding domains. Structural and functional properties revealed by limited proteolysis. J. Biol. Chem. 271, 21672-21680. 

In any case, exceptions to the FIAM have been pointed out [2,11,38,44,74,76,78]. For example, the uptake has been shown to depend on the Cj M or rMI (e.g. in the case of siderophores [11] or hydrophobic complexes [43,50]), rather than on the free c M. Several authors [11,12,15] showed that a scheme taking into account the kinetics of parallel transfer of M from several solution complexes to the internalisation transporter ( ligand exchange ) can lead to exceptions to the FIAM, even if there is no diffusion limitation. Adsorption equilibrium has been assumed in all the models discussed so far in this chapter, and the consideration of adsorption kinetics is kept for Section 4. Within the framework of the usual hypotheses in this Section 3, we would expect that the FIAM is less likely to apply for larger radii and smaller diffusion coefficients (perhaps arising from D due to the labile complexation of M with a large macromolecule or a colloid particle, see Section 3.3). 

The experiment in Figure 13-3 illustrates the use of flow cytometry to determine Kj and B ax values for binding of the es nucleoside transporter ligand, SAENTA-fiuorescein, at sites in human CEM leukemic lymphoblasts. The es nucleoside transporter is widely expressed in mammalian cells, and is concentrated in regions in the CNS that coordinately express adenosine Ai receptors (Jennings et al., 2001). 

F]Fluorobenzophenones are also precursors, after reduction into the corresponding alcohol, of different complex structures such as a 5-HT2A receptor ligand [180] and several dopamine transporter ligands GBR 13119 [181], GBR 12909 [182] and analogues [183], NNC 12-0817 and 12-0818 [184] (Scheme 40). 

In iron-deficient rats, nickel enhanced the absorption of iron (Nielsen 1980 Nielsen et al. 1980, 1984). This effect of nickel was only observed when ferric sulfate was given. No interaction was observed when iron was given as a 60% ferric/40% ferrous sulfate mixture. It has been proposed that nickel facilitates the passive diffusion of ferric ions by stabilizing the transport ligand (Nielsen 1980). 

J. M. Hoffman, S.T. Grafton, C.D. Kilts, M.M. Goodman, Initial human PET Imaging studies with the dopamine transporter ligand F-FECNT, J. Nucl. Med. 44 (2003) 855-861. 

Single photon computed emission tomography (SPECT) with the highly selective DA transporter ligand [i l] altropane was used to compare 6 adults with ADHD with a database of 30 healthy controls (Dougherty et al., 1999). Striatal binding potential (Bi ,3,j / K ) was elevated in all six ADHD patients. However, this report was questioned because 4 of the 6 patients had been previously treated with stimulants, even though they were all medication-free for at least 1 month. 

Poyot T, Conde F, Gregoire MC, Frouin V, Coulon C, Fuseau C, Hinnen F, Dolle F, Hantraye P, Bottlaender M (2001) Anatomic and biochemical correlates of the dopamine transporter ligand 11C-PE2I in normal and parkinsonian primates comparison with 6-[18F]fluoro-L-dopa. J Cereb Blood Flow Metab 27 782-792. 

Zinc metabolism Is a dynamic process which cannot be fully defined by any single static measurement. Since It is related In part to absorption, zinc bloavallablllty can be reduced by abnormalities In the gastrointestinal tract. In transport ligands or substances In the Intestinal contents which Interfere with zinc absorption. Bloavallablllty can also be affected by metabolic defects which prevent zinc uptake or utilization after absorption and by several additional factors. Some of these additional factors have been considered by previous Investigators and include age, sex, food and the Initial conditions under which bloavallablllty and metabolism were determined. 

If kj k n, then an equilibrium between the metal bound to the metal transport ligand and that in the water can be inferred (AT = kjkj) the uptake rate, determined by the free metal-ion concentration, is slow compared to the establishment of all other complex formation equilibria. 

Wellsow, J., Machulla, H.-J. and Kovar, K.-A. (2002) 3D QSAR of serotonin transporter ligands CoMFA and CoMSIA studies. Quant. Struct. -Act. Relat., 21, 577-589. 

S is the ambient concentration of available metal, kL is the rate constant for the uptake reaction in which the metal combines with a transport ligand, whose abundance per cell is given by LT. Having drawn attention to the likelihood that the Fe-transport molecules of eukaryotic algae are membrane bound siderophores, like those of cyanobacteria, Morel etal. conclude that there is ... 

The bioavailability of zinc can be affected by abnormalities in the gastrointestinal tract and in transport ligands. A reduced absorption was noted for elderly subjects (Sandstead etal. 1982, Prasad 1995). Sand-stead etal. (1982) reported that, with age, the extent of zinc absorption in the small intestine falls from 33% to > 18%. 

Newman AH. Novel dopamine transporter ligands the state of the art. Med Chem Res 1998 8 1-11. 

A recently developed pinhole high-resolution SPECT system and a 1.5 T clinical MRI scanner with a specially developed surface coil were used for rats (n = 9) after injection of the dopamine transporter ligand I-FP-CIT. The SPECT images showed clear striatal uptake. On the MR images, cerebral and extra-cerebral structures could be easily delineated. 

Nickel might either act In an enzymatic reaction that forms a lipophilic Iron transport molecule or simply preserve a transport ligand, such as citrate, by complexlng with It until replaced by the Fe(III) Ion. 

Davis MR, Votaw JR, Bremner JD, Byas-Smith MG, Faber TL, VoU RJ, Hoffman JM, Grafton ST, Kilts CD, Goodman MM (2003) Initial human PET imaging studies with the dopamine transporter ligand F-FECNT. J Nucl Med 44 855-861... 

Acetosyringone 13341 and compound 335. a potent GAT-3 transporter ligand, are examples in which a phenolic hydroxy group of an appropriate precursor reacted with tritiomethyl iodide in the presence of either K2CO3, Na2C03 or NaOH to provide a successful synthetic route for 0-[ H ]methyl aryl ethers of high specific activity. An... 

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