Pharmacological Characterization of 2-methoxy-N-propylnorapomorphine's Interactions with D2 and D3 Dopamine Receptors

Overview

Journal Synapse

Specialty Neurology

Date 2009 Feb 17

PMID 19217026

Citations 23

Authors

Mette Skinbjerg

Yoon Namkung

Christer Halldin

Robert B Innis

David R Sibley

Affiliations

Soon will be listed here.

Abstract

Dopaminergic signaling pathways have been extensively investigated using PET imaging, primarily with antagonist radioligands of D(2) and D(3) dopamine receptors (DARs). Recently, agonist radioligands of D(2)/D(3) DARs have begun to be developed and employed. One such agonist is (R)-2-(11)CH(3)O-N-n-propylnorapomorphine (MNPA). Here, we perform a pharmacological characterization of MNPA using recombinant D(2) and D(3) DARs expressed in HEK293 cells. MNPA was found to robustly inhibit forskolin-stimulated cAMP accumulation to the same extent as dopamine in D(2) or D(3) DAR-transfected cells, indicating that it is a full agonist at both receptors. MNPA is approximately 50-fold more potent than dopamine at the D(2) DAR, but equally potent as dopamine at the D(3) DAR. MNPA competition binding curves in membrane preparations expressing D(2) DARs revealed two binding states of high and low-affinity. In the presence of GTP, only one binding state of low affinity was observed. Direct saturation binding assays using [(3)H]MNPA revealed similar results as with the competition experiments leading to the conclusion that MNPA binds to the D(2) DAR in an agonist-specific fashion. In contrast to membrane preparations, using intact cell binding assays, only one site of low affinity was observed for MNPA and other agonists binding to the D(2) DAR. MNPA was also found to induce D(2) DAR internalization to an even greater extent than dopamine as determined using both cell surface receptor binding assays and confocal fluorescence microscopy. Taken together, our data indicate that the PET tracer, MNPA, is a full and potent agonist at both D(2) and D(3) receptors.

Citing Articles

Dopamine D3 Receptor in Parkinson Disease: A Prognosis Biomarker and an Intervention Target.

Xu J Curr Top Behav Neurosci. 2022; 60:89-107.

PMID: 35711029 PMC: 10034716. DOI: 10.1007/7854_2022_373.

Dopamine D Receptor Agonist Binding Kinetics-Role of a Conserved Serine Residue.

Agren R, Stepniewski T, Zeberg H, Selent J, Sahlholm K Int J Mol Sci. 2021; 22(8).

PMID: 33920848 PMC: 8071183. DOI: 10.3390/ijms22084078.

The High Affinity Dopamine D Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders.

Subburaju S, Sromek A, Seeman P, Neumeyer J ACS Chem Neurosci. 2021; 12(8):1428-1437.

PMID: 33844498 PMC: 8426090. DOI: 10.1021/acschemneuro.1c00094.

Is There a Role for GPCR Agonist Radiotracers in PET Neuroimaging?.

Colom M, Vidal B, Zimmer L Front Mol Neurosci. 2019; 12:255.

PMID: 31680859 PMC: 6813225. DOI: 10.3389/fnmol.2019.00255.

Hunting for the high-affinity state of G-protein-coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging.

Shalgunov V, van Waarde A, Booij J, Michel M, Dierckx R, Elsinga P Med Res Rev. 2018; 39(3):1014-1052.

PMID: 30450619 PMC: 6587759. DOI: 10.1002/med.21552.

References

Vanhauwe J, Fraeyman N, Francken B, Luyten W, Leysen J . Comparison of the ligand binding and signaling properties of human dopamine D(2) and D(3) receptors in Chinese hamster ovary cells. J Pharmacol Exp Ther. 1999; 290(2):908-16. View

McCarron J, Zoghbi S, Shetty H, Vermeulen E, Wikstrom H, Ichise M . Synthesis and initial evaluation of [11C](R)-RWAY in monkey-a new, simply labeled antagonist radioligand for imaging brain 5-HT1A receptors with PET. Eur J Nucl Med Mol Imaging. 2007; 34(10):1670-82. DOI: 10.1007/s00259-007-0460-z. View

Watts V, Neve K . Sensitization of endogenous and recombinant adenylate cyclase by activation of D2 dopamine receptors. Mol Pharmacol. 1996; 50(4):966-76. View

Murray A, Ryoo H, Gurevich E, Joyce J . Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain. Proc Natl Acad Sci U S A. 1994; 91(23):11271-5. PMC: 45209. DOI: 10.1073/pnas.91.23.11271. View

Seeman P . Dopamine D2(High) receptors on intact cells. Synapse. 2008; 62(4):314-8. DOI: 10.1002/syn.20499. View

Mukherjee J, Narayanan T, Christian B, Shi B, Yang Z . Binding characteristics of high-affinity dopamine D2/D3 receptor agonists, 11C-PPHT and 11C-ZYY-339 in rodents and imaging in non-human primates by PET. Synapse. 2004; 54(2):83-91. DOI: 10.1002/syn.20068. View

Narendran R, Hwang D, Slifstein M, Talbot P, Erritzoe D, Huang Y . In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride. Synapse. 2004; 52(3):188-208. DOI: 10.1002/syn.20013. View

Namkung Y, Sibley D . Protein kinase C mediates phosphorylation, desensitization, and trafficking of the D2 dopamine receptor. J Biol Chem. 2004; 279(47):49533-41. DOI: 10.1074/jbc.M408319200. View

Castro S, Strange P . Coupling of D2 and D3 dopamine receptors to G-proteins. FEBS Lett. 1993; 315(3):223-6. DOI: 10.1016/0014-5793(93)81168-y. View

10.

Chio C, Lajiness M, Huff R . Activation of heterologously expressed D3 dopamine receptors: comparison with D2 dopamine receptors. Mol Pharmacol. 1994; 45(1):51-60. View

11.

Macey T, Gurevich V, Neve K . Preferential Interaction between the dopamine D2 receptor and Arrestin2 in neostriatal neurons. Mol Pharmacol. 2004; 66(6):1635-42. DOI: 10.1124/mol.104.001495. View

12.

Sokoloff P, Giros B, Martres M, Bouthenet M, Schwartz J . Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 1990; 347(6289):146-51. DOI: 10.1038/347146a0. View

13.

Narendran R, Hwang D, Slifstein M, Hwang Y, Huang Y, Ekelund J . Measurement of the proportion of D2 receptors configured in state of high affinity for agonists in vivo: a positron emission tomography study using [11C]N-propyl-norapomorphine and [11C]raclopride in baboons. J Pharmacol Exp Ther. 2005; 315(1):80-90. DOI: 10.1124/jpet.105.090068. View

14.

Ferguson S . Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev. 2001; 53(1):1-24. View

15.

Marchese A, Paing M, Temple B, Trejo J . G protein-coupled receptor sorting to endosomes and lysosomes. Annu Rev Pharmacol Toxicol. 2007; 48:601-29. PMC: 2869288. DOI: 10.1146/annurev.pharmtox.48.113006.094646. View

16.

Goggi J, Sardini A, Egerton A, Strange P, Grasby P . Agonist-dependent internalization of D2 receptors: Imaging quantification by confocal microscopy. Synapse. 2007; 61(4):231-41. DOI: 10.1002/syn.20360. View

17.

Narendran R, Slifstein M, Hwang D, Hwang Y, Scher E, Reeder S . Amphetamine-induced dopamine release: duration of action as assessed with the D2/3 receptor agonist radiotracer (-)-N-[(11)C]propyl-norapomorphine ([11C]NPA) in an anesthetized nonhuman primate. Synapse. 2006; 61(2):106-9. DOI: 10.1002/syn.20346. View

18.

Groer C, Tidgewell K, Moyer R, Harding W, Rothman R, Prisinzano T . An opioid agonist that does not induce mu-opioid receptor--arrestin interactions or receptor internalization. Mol Pharmacol. 2006; 71(2):549-57. PMC: 3926195. DOI: 10.1124/mol.106.028258. View

19.

Willeit M, Ginovart N, Kapur S, Houle S, Hussey D, Seeman P . High-affinity states of human brain dopamine D2/3 receptors imaged by the agonist [11C]-(+)-PHNO. Biol Psychiatry. 2005; 59(5):389-94. DOI: 10.1016/j.biopsych.2005.09.017. View

20.

Yasuno F, Zoghbi S, McCarron J, Hong J, Ichise M, Brown A . Quantification of serotonin 5-HT1A receptors in monkey brain with [11C](R)-(-)-RWAY. Synapse. 2006; 60(7):510-20. DOI: 10.1002/syn.20327. View