ESTONIAN ACADEMY
PUBLISHERS
eesti teaduste
akadeemia kirjastus
PUBLISHED
SINCE 1952
 
Proceeding cover
proceedings
of the estonian academy of sciences
ISSN 1736-7530 (Electronic)
ISSN 1736-6046 (Print)
Impact Factor (2022): 0.9
Research article
Inhibition of ligand–protein complex isomerization by some dopamine transporter inhibitors; pp. 402–406
PDF | https://doi.org/10.3176/proc.2023.4.05

Author
Siim Kukk
Abstract

Kinetic analysis of the interaction of four N­substituted nortropane derivatives with the dopamine transporter was made to characterize the mechanism of the binding process. The kinetics were studied by radioligand binding experiments. It was found that the studied compounds initiate a slow isomerization process of the initially formed ligand–transporter complex, but at higher concentrations, the same compounds inhibit the isomerization process. The results suggest that the studied ligands interact with two distinct binding sites of the transporter protein that have different ligand binding specificities. The interaction of ligands with different binding sites must be taken into consideration when analyzing the ligand recognition patterns of the transporter protein.

References

1. Strickland, S., Palmer, G. and Massey, V. Determination of dissociation constants and specific rate constants of enzyme–substrate (or protein–ligand) interactions from rapid reaction kinetic data. J. Biol. Chem., 1975, 250(11), 4048–4052. 
https://doi.org/10.1016/S0021-9258(19)41384-7

2. Järv, J., Hedlund, B. and Bartfai, T. Isomerization of the muscarinic receptor–antagonist complex. J. Biol. Chem., 1979, 254(13), 5595–5598. 
https://doi.org/10.1016/S0021-9258(18)50452-X

3. Abele, R., Keinänen, K. and Madden, D. R. Agonist-induced isomerization in a glutamate receptor ligand-binding domain: a kinetic and mutagenetic analysis. J. Biol. Chem., 2000, 275(28), 21355–21363. 
https://doi.org/10.1074/jbc.M909883199

4. Chappell, D. A., Fry, G. L., Waknitz, M. A. and Berns, J. J. Evidence for isomerization during binding of apolipopro­tein-B100 to low density lipoprotein receptors. J. Biol. Chem., 1992, 267(1), 270–279. 
https://doi.org/10.1016/S0021-9258(18)48489-X

5. Schliebs, R. and Bigl, V. Kinetics of the interaction of dihydroalprenolol with beta-adrenergic receptors in rat cerebral cortex. Gen. Physiol. Biophys., 1984, 3(1), 31–46.

6. Lepiku, M., Rinken, A., Järv, J. and Fuxe, K. Kinetic evidence for isomerization of the dopamine receptor–raclopride complex. Neurochem. Int., 1996, 28(5–6), 591–595. 
https://doi.org/10.1016/0197-0186(95)00123-9

7. Järv, J. Neurotoxic agents interacting with the muscarinic acetylcholine receptor. In Selective Neurotoxicity (Herken, H. and Hucho, F., eds). Springer, Berlin, Heidelberg, 1994, 659–680. 
https://doi.org/10.1007/978-3-642-85117-9_18

8. Stepanov, V. and Järv, J. Slow isomerization step in the interaction between mouse dopamine transporter and dopa­mine re-uptake inhibitor N-(3-iodoprop-2E-enyl)-2β-carbo-[3H]methoxy-3β-(4′-methylphenyl)nortropane. Neurosci. Lett., 2006, 410(3), 218–221. 
https://doi.org/10.1016/j.neulet.2006.10.007

9. Kukk, S. and Järv, J. Small structural changes at the N-position of the tropane core control the mechanism of nortropane derivatives binding to dopamine transporter. ChemistrySelect, 2018, 3(23), 6581–6584. 
https://doi.org/10.1002/slct.201801532

10. Reed, M. C., Lieb, A. and Nijhout, H. F. The biological significance of substrate inhibition: a mechanism with di­verse functions. BioEssays, 2010, 32(5), 422–429. 
https://doi.org/10.1002/bies.200900167

11. Emond, P., Garreau, L., Chalon, S., Boazi, M., Caillet, M., Bricard, J. et al. Synthesis and ligand binding of nortropane derivatives: N-substituted 2β-carbomethoxy-3β-(4‘-iodo­phenyl)nortropane and N-(3-Iodoprop-(2E)-enyl)-2β-carbome­thoxy-3β-(3‘,4‘-disubstituted phenyl)nortropane. New high-affinity and selective compounds for the dopamine transporter. J. Med. Chem., 1997, 40(9), 1366–1372. 
https://doi.org/10.1021/jm960795d

12. Xu, L. and Trudell, M. L. Stereoselective synthesis of 2β-carbomethoxy-3β-phenyltropane derivatives. Enhanced stereo­selectivity observed for the conjugate addition reaction of phenylmagnesium bromide derivatives with anhydro di­chloromethane. J. Heterocycl. Chem., 1996, 33(6), 2037–2039. 
https://doi.org/10.1002/jhet.5570330676

13. Moore, J. L., Taylor, S. M. and Soloshonok, V. A. An efficient and operationally convenient general synthesis of tertiary amines by direct alkylation of secondary amines with alkyl halides in the presence of Huenig’s base. Arkivoc, 2005, 2005(6), 287–292. 
https://doi.org/10.3998/ark.5550190.0006.624

14. Page, G., Chalon, S., Emond, P., Maloteaux, J.-M. and Hermans, E. Pharmacological characterisation of (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)nortropane (PE2I) binding to the rat neuronal dopamine transporter expressed in COS cells. Neurochem. Int., 2002, 40(2), 105–113. 
https://doi.org/10.1016/S0197-0186(01)00086-9

15. Stepanov, V., Schou, M., Järv, J. and Halldin, C. Synthesis of 3H-labeled N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane (PE2I) and its interaction with mice striatal membrane fragments. Appl. Radiat. Isot., 2007, 65(3), 293–300. 
https://doi.org/10.1016/j.apradiso.2006.09.003

16. Kukk, S. and Järv, J. Differentiating between drugs with short and long residence times. MedChemComm, 2016, 7(8), 1654–1656. 
https://doi.org/10.1039/C6MD00269B

17. Kukk, S., Järv, J. and Miidla, P. Kinetic tools for the identification of ligand–receptor interaction mechanisms. Proc. Est. Acad. Sci., 2017, 66(2), 202–213. 
https://doi.org/10.3176/proc.2017.2.08

18. Nepal, B., Das, S., Reith, M. E. and Kortagere, S. Overview of the structure and function of the dopamine transporter and its protein interactions. Front. Physiol., 2023, 14, 1150355. 
https://doi.org/10.3389/fphys.2023.1150355

19. Rothman, R. B., Dersch, C. M., Ananthan, S. and Partilla, J. S. Studies of the biogenic amine transporters. 13. Identification of “Agonist” and “Antagonist” allosteric modulators of amphetamine-induced dopamine release. J. Pharmacol. Exp. Ther., 2009, 329(2), 718–728. 
https://doi.org/10.1124/jpet.108.149088

20. Rothman, R. B., Ananthan, S., Partilla, J. S., Saini, S. K., Moukha-Chafiq, O., Pathak, V. et al. Studies of the biogenic amine transporters 15. Identification of novel allosteric dopamine transporter ligands with nanomolar potency. J. Pharmacol. Exp. Ther., 2015, 353(3), 529–538. 
https://doi.org/10.1124/jpet.114.222299

Back to Issue