Roxindole hydrochloride

Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors.[Pubmed:10431754]

Naunyn Schmiedebergs Arch Pharmacol. 1999 Jun;359(6):447-53.

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.

Roxindole: psychopharmacological profile of a dopamine D2 autoreceptor agonist.[Pubmed:8558454]

J Pharmacol Exp Ther. 1996 Jan;276(1):41-8.

The putative, selective dopamine (DA) dopamine-2 autoreceptor agonist roxindole, which also exhibits serotonin-1A-agonistic and 5-hydroxytryptamine reuptake-inhibiting properties, was examined for its behavioral effects in rats and mice. Roxindole inhibited apomorphine-induced climbing in mice and stereotyped behavior in rats with ED50 values of 1.4 mg/kg s.c. and 0.65 mg/kg s.c., respectively, and inhibited conditioned avoidance response in rats (ED50 = 1.5 mg/kg s.c.). Thus roxindole showed a profile resembling those of the classical antipsychotic haloperidol and the atypical neuroleptic clozapine but differing from that of the DA autoreceptor agonist talipexole, which did not prevent apomorphine-induced behaviors. Unlike haloperidol, roxindole did not induce catalepsy in rats and mice. Investigations directed to the DA autoreceptor properties revealed that spontaneous motility of rats with normosensitive postsynaptic DA receptors was monophasically decreased by roxindole and talipexole, with a threshold dose of 0.0625 mg/kg s.c. for both compounds. In reserpinized rats with presumably hypersensitive postsynaptic DA receptors, roxindole only partially reversed reserpine-induced hypomotility (threshold dose: 0.25 mg/kg); talipexole re-established the activity level to that of normal rats. In contrast to apomorphine, roxindole did not induce and talipexole only marginally induced stereotyped behavior in normal rats. After administration of the DA dopamine-1 agonist SKF 38393, talipexole induced stereotyped behavior in rats, which indicated its activity at postsynaptic dopamine-2 receptors. In contrast, roxindole did not induce stereotyped behavior in rats when co-administered with SKF 38393. These results indicate that, compared with talipexole, roxindole possesses a greater selectivity for DA autoreceptors.

Biochemical and functional studies on EMD 49,980: a potent, selectively presynaptic D-2 dopamine agonist with actions on serotonin systems.[Pubmed:2565817]

Eur J Pharmacol. 1989 Jan 24;160(1):31-41.

EMD 49,980 proved to be a potent and selectively presynaptic D-2 dopamine receptor agonist in biochemical studies with rats. Thus, the gamma-butyrolactone-induced accumulation of dihydroxyphenylalanine, used as a presynaptic model, was antagonized with ED50 values of 0.29 and 0.09 mumol/kg in striatum and t. olfactorium, respectively, with high maximal effects. In contrast, striatal acetylcholine concentrations, reflecting actions at normosensitive postsynaptic D-2 receptors, were only moderately increased by about 30% over a dose range of 2.3-68 mumol/kg. In rats with unilateral nigrostriatal lesions, EMD 49,980 induced long-lasting contralateral turning, indicative of agonistic actions at denervated postsynaptic D-2 receptors. In addition, EMD 49,980 potently inhibited serotonin (5-HT) uptake in vitro and in vivo. Binding studies confirmed D-2 activity in the nM range but, similarly potent effects were observed at 5-HT1A binding sites. Measurement of 5-hydroxytryptophan (5-HTP) accumulation in the n. raphe revealed that, in vivo, the net effect of EMD 49,980 on 5-HT systems is an agonistic one. Control experiments indicate that inhibition of 5-HTP accumulation by EMD 49,980 is induced mainly via direct activation of 5-HT1A receptors, although some contribution due to 5-HT uptake inhibition is likely. Furthermore, results with various reference compounds make it unlikely that there are indirect effects, also via alpha 2-receptors in the models used and support the view that D-2 agonistic, 5-HT uptake inhibiting and 5-HT1A agonistic actions are independent properties of EMD 49,980.