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Dopamine D2 receptors selectively labeled by a benzamide neuroleptic: [3H]-YM-09151-2

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Summary

In order to label dopamine D2 receptors selectively we tritiated the potent benzamide neuroleptic, YM-09151-2 (26.7 Ci/mmol). The binding of [3H]-YM-09151-2 to canine striatal membranes was saturable and specific with a K D of 57 pmol/l and B max of 36 pmol/g tissue as determined by Scatchard analysis. The K D, but not the B max, of [3H]-YM-09151-2 increased 6-fold in the absence of sodium chloride. [3H]-YM-09151-2 labeled 40% more sites than [3H]-spiperone in the same tissue homogenate. [3H]-YM-09151-2 binding was inhibited by dopaminergic drugs in a concentration and stereoselective manner with the appropriate dopamine D2 receptor profile. Thus, dopamine agonists inhibited [3H]-YM-09151-2 binding to canine striatal membranes with the following rank order of potency: (−)-N-n-propylnorapomorphine > apomorphine > (±)-6,7-dihydroxy-2-aminotetralin > (+)-N-n-propylnorapomorphine > dopamine > (−)-noradrenaline > serotonin > (−)-isoprenaline. Dopaminergic antagonists competed for [3H]-YM-09151-2 binding with the following order of potency: spiperone > (+)-butaclamol > haloperidol > clebopride > (−)-sulpiride > SCH-23390 > (−)-butaclamol. Furthermore, dopamine agonists recognized 2 states of the receptor labeled by [3H]-YM-09151-2, D high2 and D low2 . The D high2 state of the receptor could be converted to D low2 by guanine nucleotides and sodium ions as is the case for [3H]-spiperone binding to D2 receptors. [3H]-YM-09151-2 appears to be a more selective ligand for dopamine D2 receptors than [3H]-spiperone, since YM-09151-2 displays approximately 9-fold lower affinity than spiperone for cortical serotonergic (S2) receptors. [3H]-YM-09151-2 may become a useful tool for the selective characterization of dopamine D2 receptors.

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Abbreviations

(±)ADTN:

(±)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene

NPA:

N-n-propylnorapomorphine

Gpp(NH)p:

5′-guanylylimidodiphosphate

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, University of Toronto, M5S 1A8, Toronto, Ontario, Canada

    H. B. Niznik, D. E. Grigoriadis & P. Seeman

  2. Radiochemistry Department, Nuclear Research Center, Negev, P.O. Box 9001, Beer-Sheva, Israel

    I. Pri-Bar & O. Buchman

Authors
  1. H. B. Niznik
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  2. D. E. Grigoriadis
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  3. I. Pri-Bar
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  4. O. Buchman
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  5. P. Seeman
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Niznik, H.B., Grigoriadis, D.E., Pri-Bar, I. et al. Dopamine D2 receptors selectively labeled by a benzamide neuroleptic: [3H]-YM-09151-2. Naunyn-Schmiedeberg's Arch. Pharmacol. 329, 333–343 (1985). https://doi.org/10.1007/BF00496365

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  • DOI: https://doi.org/10.1007/BF00496365

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