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Identification and Characterization of a Novel Class of Atypical Dopamine Receptor Agonists

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Abstract

Purpose

The D3 dopamine receptor exhibits tolerance and slow response termination (SRT) properties that are not exhibited by the closely-related D2 dopamine receptor. We previously demonstrated that the induction of tolerance elicits a unique conformational change in the D3 receptor. Here we tested the hypothesis that the tolerance and SRT properties of the D3 receptor are ligand-dependent.

Methods

We used pharmacophore modeling and in silico screening approaches coupled with electrophysiological and biochemical methods to identify and functionally characterize the novel dopamine receptor agonists.

Results

We identified cis-8-OH-PBZI (PBZI), FAUC73 and an additional novel compound, ES609, which although they are full D3 receptor agonists, do not induce the tolerance and SRT properties of the D3 receptor. In addition, PBZI has full intrinsic activity at D2L, is a partial agonist at D2S and exhibits functional selectivity at D4.2 dopamine receptors. ES609 is a partial agonist at D2S, D2L and D4.2 receptors, and exhibits functional selectivity at D2L and D4.2 dopamine receptors.

Conclusion

We have discovered a novel class of atypical dopamine receptor agonists that include three structurally dissimilar compounds. These new agonists will help determine the physiological and pathophysiological relevance of D3 receptor tolerance and SRT properties.

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Abbreviations

cAMP:

cyclic adenosine monophosphate

EC:

extracellular

EC50 :

half-maximal effective concentration

GIRK:

G protein–coupled inward rectifier potassium

GPCR:

G protein–coupled receptor

hERG:

human ether-à-go-go related gene

HSB:

hybrid structure–based

IBMX:

3-isobutyl-1-methylxanthine

IC:

intracellular

MAP:

mitogen-activated protein

MD:

molecular dynamics

OPLS:

optimized potentials for liquid simulations

PBZI:

cis-8-hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-1H-benz[e]indole hydrobromide

POPC:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

RMSD:

root mean square deviation

SRT:

slow response termination

TM:

transmembrane

β2-AR:

β2-adrenergic receptor

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ACKNOWLEDGMENTS & DISCLOSURES

This work was supported by the UMDNJ and the F. M. Kirby Foundations to EVK and American Heart Association–scientist development grant and Faculty start-up funds from Drexel University College of Medicine to SK. We thank Diana Winters (Academic Publishing Services, Drexel University College of Medicine) for proof-reading the manuscript. The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacology & Physiology, UMDNJ-New Jersey Medical School, MSB, I-647, 185 South Orange Avenue, Newark, New Jersey, 07103, USA

    E. V. Kuzhikandathil

  2. Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, 19129, USA

    S. Kortagere

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  1. E. V. Kuzhikandathil
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Correspondence to E. V. Kuzhikandathil.

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Supplementary Figure 1

(A) FAUC73 and PBZI do not induce GIRK currents in parental AtT-20. Representative voltage clamp recording shows that neither 300 nM FAUC73 (open hatched bar) nor 300 nM PBZI (gray hatched bar) induce GIRK currents in parental AtT-20 cells in the absence of exogenous D3 receptor expression. (B) D2/D3 receptor antagonist blocks PBZI-induced GIRK response in AtT-20 cells expressing human D3 receptors. Representative voltage clamp recording shows that 100 nM eticlopride blocks the GIRK currents induced by 300 nM PBZI (gray hatched bar) in AtT-20 cells expressing the human D3 receptor. All ligands were applied in elevated extracellular potassium (30 K) to enhance the inward rectifying GIRK currents. (C) The inability of PBZI to induce D3 receptor tolerance is independent of agonist concentration. Cumulative data shows the ratio of second to first agonist-induced GIRK response in AtT-20 cells stably expressing the human D3 dopamine receptor. The AtT-D3 cells were treated with 100 nM dopamine (DA) or PBZI at a concentration that ranged from 100 nM to 10,000 nM. For these experiments, the concentration of agonist applied was the same for the first and second application. The agonists were applied for 60 s. Error bars represent ± SEM. *, P < 0.05, ANOVA, post-hoc Holm-Sidak test comparing dopamine (DA) to all the PBZI responses. (TIFF 1283 kb)

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Kuzhikandathil, E.V., Kortagere, S. Identification and Characterization of a Novel Class of Atypical Dopamine Receptor Agonists. Pharm Res 29, 2264–2275 (2012). https://doi.org/10.1007/s11095-012-0754-0

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  • DOI: https://doi.org/10.1007/s11095-012-0754-0

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