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Article

Dopamine D2 Receptor Agonist Binding Kinetics—Role of a Conserved Serine Residue

1
Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
2
Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM)—Pompeu Fabra University (UPF), 08003 Barcelona, Spain
3
InterAx Biotech AG, 5234 Villigen, Switzerland
4
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 02-089 Warsaw, Poland
5
Department of Integrative Medical Biology, Wallenberg Centre for Molecular Medicine, Umeå University, 901 87 Umeå, Sweden
*
Authors to whom correspondence should be addressed.
Academic Editor: Alexandre G. de Brevern
Int. J. Mol. Sci. 2021, 22(8), 4078; https://doi.org/10.3390/ijms22084078
Received: 10 March 2021 / Revised: 6 April 2021 / Accepted: 13 April 2021 / Published: 15 April 2021
(This article belongs to the Special Issue Function of Neurotransmitter Receptors in Health and Disease)
The forward (kon) and reverse (koff) rate constants of drug–target interactions have important implications for therapeutic efficacy. Hence, time-resolved assays capable of measuring these binding rate constants may be informative to drug discovery efforts. Here, we used an ion channel activation assay to estimate the kons and koffs of four dopamine D2 receptor (D2R) agonists; dopamine (DA), p-tyramine, (R)- and (S)-5-OH-dipropylaminotetralin (DPAT). We further probed the role of the conserved serine S1935.42 by mutagenesis, taking advantage of the preferential interaction of (S)-, but not (R)-5-OH-DPAT with this residue. Results suggested similar koffs for the two 5-OH-DPAT enantiomers at wild-type (WT) D2R, both being slower than the koffs of DA and p-tyramine. Conversely, the kon of (S)-5-OH-DPAT was estimated to be higher than that of (R)-5-OH-DPAT, in agreement with the higher potency of the (S)-enantiomer. Furthermore, S1935.42A mutation lowered the kon of (S)-5-OH-DPAT and reduced the potency difference between the two 5-OH-DPAT enantiomers. Kinetic Kds derived from the koff and kon estimates correlated well with EC50 values for all four compounds across four orders of magnitude, strengthening the notion that our assay captured meaningful information about binding kinetics. The approach presented here may thus prove valuable for characterizing D2R agonist candidate drugs. View Full-Text
Keywords: Xenopus oocytes; electrophysiology; voltage-clamp; molecular dynamics simulation; G protein-coupled receptor; phenethylamines; aminotetralins Xenopus oocytes; electrophysiology; voltage-clamp; molecular dynamics simulation; G protein-coupled receptor; phenethylamines; aminotetralins
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MDPI and ACS Style

Ågren, R.; Stepniewski, T.M.; Zeberg, H.; Selent, J.; Sahlholm, K. Dopamine D2 Receptor Agonist Binding Kinetics—Role of a Conserved Serine Residue. Int. J. Mol. Sci. 2021, 22, 4078. https://doi.org/10.3390/ijms22084078

AMA Style

Ågren R, Stepniewski TM, Zeberg H, Selent J, Sahlholm K. Dopamine D2 Receptor Agonist Binding Kinetics—Role of a Conserved Serine Residue. International Journal of Molecular Sciences. 2021; 22(8):4078. https://doi.org/10.3390/ijms22084078

Chicago/Turabian Style

Ågren, Richard, Tomasz M. Stepniewski, Hugo Zeberg, Jana Selent, and Kristoffer Sahlholm. 2021. "Dopamine D2 Receptor Agonist Binding Kinetics—Role of a Conserved Serine Residue" International Journal of Molecular Sciences 22, no. 8: 4078. https://doi.org/10.3390/ijms22084078

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