title: Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors.
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 (pKi values 8.93, 8.55 and 8.23, respectively). Further, it displayed high affinity at hS-HT1A receptors (pKi = 9.42) but modest affinity at 5-HT1B and 5-HT1D receptors (pKi values 6.00 and 7.05, respectively). In [35S]GTPgammaS binding experiments, roxindole was >20-fold more potent in stimulating [35S]GTPgammaS 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 (Emax = 30.0% and 35.1%, respectively, relative to dopamine = 100%), it only weakly activated hD2 receptors (Emax = 10.5%). Roxindole potently blocked dopamine-stimulated [35S]GTPgammaS binding at hD2 receptors (pkappaB = 9.05). In comparison, the dopamine receptor agonist, (-)quinpirole, acted as a partial agonist at hD3 and hD4 sites (Emax = 67.4% and 66.3%, respectively) but surpassed the efficacy of dopamine at hD2 receptors (Emax = 132%). At h5-HT1A receptors, roxindole behaved as a high affinity (pKi = 9.42) partial agonist (Emax = 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]GTPgammaS binding at h5-HT1A receptors in a concentration-dependent manner (pkappaB = 9.28). Roxindole only weakly stimulated [35S]GTPgammaS binding at 5-HT1B and 5-HT1D receptors (Emax = 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.
authors.affiliation: Psychopharmacology Department, Institut de Recherches Servier, Croissy-sur-Seine (Paris), France. newman_tancredi@hotmail.com
authors.forename: A
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: D
authors.initials: D
authors.lastname: Cussac
authors.forename: V
authors.initials: V
authors.lastname: Audinot
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D000078183:Oxindoles; D011725:Pyridines / Q000494:pharmacology*; D019257:Quinpirole / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; C493593:DRD3 protein, human; C493599:DRD4 protein, human; D018491:Dopamine Agonists; C470302:HTR1B protein, human; D007211:Indoles; D000078183:Oxindoles; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins; D050638:Receptors, Dopamine D4; D019257:Quinpirole; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C059613:roxindole