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Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors

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Abstract

Roxindole is a potential antidepressant agent. The present study determined its affinity and agonist efficacy at recombinant human (h) dopamine hD2, hD3 and hD4 and serotonin (5-HT) h5-HT1A, h5-HT1B and h5-HT1D receptors. Roxindole exhibited high affinity at hD3 as well as at hD2 (short isoform) and hD4 (4-repeat isoform) receptors (pK i values 8.93, 8.55 and 8.23, respectively). Further, it displayed high affinity at h5-HT1A receptors (pK i = 9.42) but modest affinity at 5-HT1B and 5-HT1D receptors (pK i values 6.00 and 7.05, respectively). In [35S]GTPγS binding experiments, roxindole was >20-fold more potent in stimulating [35S]GTPγS binding at hD3 than at hD2 or hD4 receptors (pEC50 = 9.23 vs. 7.88 and 7.69). However, whereas roxindole exhibited partial agonist activity at hD3 and hD4 sites (E max = 30.0% and 35.1%, respectively, relative to dopamine = 100%), it only weakly activated hD2 receptors (E max = 10.5%). Roxindole potently blocked dopamine-stimulated [35S]GTPγS binding at hD2 receptors (pK B = 9.05). In comparison, the dopamine receptor agonist, (-)quinpirole, acted as a partial agonist at hD3 and hD4 sites (E max = 67.4% and 66.3%, respectively) but surpassed the efficacy of dopamine at hD2 receptors (E max = 132%). At h5-HT1A receptors, roxindole behaved as a high affinity (pK i = 9.42) partial agonist (E max = 59.6%, relative to 5-HT = 100%), whereas (-)quinpirole had negligible activity. The selective 5-HT1A antagonist, WAY 100,635, blocked roxindole (100 nM)-stimulated [35S]GTPγS binding at h5-HT1A receptors in a concentration-dependent manner (pK B = 9.28). Roxindole only weakly stimulated [35S]GTPγS binding at 5-HT1B and 5-HT1D receptors (E max = 27.1% and 13.7%). The present data suggest that roxindole activates mainly D3 vs. D2 or D4 receptors and 5-HT1A vs. 5-HT1B or 5-HT1D receptors. Activation of D3 and/or 5-HT1A receptors may thus contribute to its potential antidepressant properties.

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Received: 4 February 1999 / Accepted: 29 March 1999

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Newman-Tancredi, A., Cussac, D., Audinot, V. et al. Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors. Naunyn-Schmiedeberg's Arch Pharmacol 359, 447–453 (1999). https://doi.org/10.1007/PL00005374

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  • DOI: https://doi.org/10.1007/PL00005374

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