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

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-HT_1A, h5-HT_1B and h5-HT_1D 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-HT_1A receptors (pK _i = 9.42) but modest affinity at 5-HT_1B and 5-HT_1D 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-HT_1A 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-HT_1A antagonist, WAY 100,635, blocked roxindole (100 nM)-stimulated [³⁵S]GTPγS binding at h5-HT_1A receptors in a concentration-dependent manner (pK _B = 9.28). Roxindole only weakly stimulated [³⁵S]GTPγS binding at 5-HT_1B and 5-HT_1D receptors (E _max = 27.1% and 13.7%). The present data suggest that roxindole activates mainly D₃ vs. D₂ or D₄ receptors and 5-HT_1A vs. 5-HT_1B or 5-HT_1D receptors. Activation of D₃ and/or 5-HT_1A receptors may thus contribute to its potential antidepressant properties. Received: 4 February 1999 / Accepted: 29 March 1999