Sumanirole maleate

Sumanirole maleate is a highly selective agonist of dopamine D2 with EC50 values ranging from 17 to 75 nM. Sumanirole showed 200-fold selectivity over other dopamine receptor subtypes in cell-based assays [1].

In vitro, sumanirole inhibited Forskolin-stimulated cAMP accumulation in Chinese hamster ovary (CHO) cells. Sumanirole could activate mitogenesis stimulated by D2 receptor with an EC50 value of 4.6 nM [1].

In vivo, sumanirole was reported to reduce prepulse inhibition (PPI) in rats at 60-120 ms prepulse intervals, while increasing the PPI at 10-20 ms prepulse intervals [2]. Besides, in male Sprague-Dawley rats, sumanirole decreased plasma prolactin levels in a dose-dependent manner and reduced dopamine neuron firing rates in the SNPC with an ED50 value of 2.3 μmol/kg [1].

References:
[1] McCall RB1, Lookingland KJ, Bédard PJ, Huff RM. Sumanirole, a highly dopamine D2-selective receptor agonist: in vitro and in vivo pharmacological characterization and efficacy in animal models of Parkinson's disease. J Pharmacol Exp Ther. 2005 Sep;314(3):1248-56.
[1] Weber M1, Chang WL, Breier MR, Yang A, Millan MJ, Swerdlow NR.The effects of the dopamine D2 agonist sumanirole on prepulse inhibition in rats. Eur Neuropsychopharmacol. 2010 Jun;20(6):421-5. doi: 10.1016/j.euroneuro.2010.02.011. Epub 2010 Mar 25.

Effect of GDNF on depressive-like behavior, spatial learning and key genes of the brain dopamine system in genetically predisposed to behavioral disorders mouse strains.[Pubmed:25101543]

Behav Brain Res. 2014 Nov 1;274:1-9.

The effect of glial cell line-derived neurotrophic factor (GDNF) on behavior and brain dopamine system in predisposed to depressive-like behavior ASC (Antidepressant Sensitive Cataleptics) mice in comparison with the parental "nondepressive" CBA mice was studied. In 7days after administration (800ng, i.c.v.) GDNF decreased escape latency time and the path traveled to reach hidden platform in Morris water maze in ASC mice. GDNF enhanced depressive-like behavioral traits in both "nondepressive" CBA and "depressive" ASC mice. In CBA mice, GDNF decreased functional response to agonists of D1 (chloro-APB hydrobromide) and D2 (Sumanirole maleate) receptors in tail suspension test, reduced D2 receptor gene expression in the substantia nigra and increased monoamine oxydase A (MAO A) gene expression in the striatum. GDNF increased D1 and D2 receptor genes expression in the nucleus accumbens of ASC mice but failed to alter expression of catechol-O-methyltransferase, dopamine transporter, MAO B and tyrosine hydroxylase genes in both investigated mouse strains. Thus, GDNF produced long-term genotype-dependent effect on behavior and the brain dopamine system. GDNF pretreatment (1) reduced D1 and D2 receptors functional responses and D2 receptor gene expression in s. nigra of CBA mice; (2) increased D1 and D2 receptor genes expression in n. accumbens of ASC mice and (3) improved spatial learning in ASC mice. GDNF enhanced depressive-like behavior both in CBA and ASC mice. The data suggest that genetically defined variance in the cross-talk between GDNF and brain dopamine system contributes to the variability of GDNF-induced responses and might be responsible for controversial GDNF effects.

Effects of dopamine D(2)-like receptor agonists in mice trained to discriminate cocaine from saline: influence of feeding condition.[Pubmed:24561049]

Eur J Pharmacol. 2014 Apr 15;729:123-31.

In rats, the discriminative stimulus effects of direct- and indirect-acting dopamine receptor agonists are mediated by multiple dopamine receptor subtypes and the relative contribution of dopamine D2 and D3 receptors to these effects varies as a function of feeding condition. In these studies, free-fed and food-restricted mice were trained to discriminate 10.0mg/kg cocaine using a two-lever discrimination procedure in which responding was maintained by food. Both groups of mice acquired the discrimination; however, free-fed mice responded at lower rates than food-restricted mice. Dopamine D3 receptor agonists, pramipexole and quinpirole, increased cocaine-appropriate responding (>85%) in food-restricted, but not in free-fed mice. The dopamine D2 receptor agonist, sumanirole, and the nonselective dopamine receptor agonist, apomorphine, failed to increase cocaine-appropriate responding in either group. Free-fed mice were more sensitive than food-restricted mice to the rate-decreasing effects of dopamine receptor agonists and these effects could not be overcome by increasing the magnitude of reinforcement. Because feeding condition did not alter quinpirole-induced hypothermia, it is unlikely that differences in the discriminative stimulus or rate-decreasing effects of dopamine D2-like receptor agonists were due to differences in the pharmacokinetic properties of the drugs. Although these results suggest that the discriminative stimulus effects of cocaine are mediated by both dopamine D2 and D3 receptors in food-restricted mice, the increased sensitivity of free-fed mice to the rate-decreasing effects of dopamine D2-like receptor agonists limited conclusions about the impact of feeding conditions on the relative contribution of dopamine D2 and D3 receptors to the discriminative stimulus effects of cocaine.

Sumanirole, a highly dopamine D2-selective receptor agonist: in vitro and in vivo pharmacological characterization and efficacy in animal models of Parkinson's disease.[Pubmed:15980060]

J Pharmacol Exp Ther. 2005 Sep;314(3):1248-56.

The purpose of this study is to demonstrate that sumanirole is a novel dopamine receptor agonist with high in vitro and in vivo selectivity for the D(2) receptor subtype. Sumanirole, (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Z)-2-butenedioate (1:1), is unique; it has greater than 200-fold selectivity for the D(2) receptor subtype versus the other dopamine receptor subtypes in radioligand binding assays. In cell-based assays, sumanirole is a fully efficacious agonist, with EC(50) values between 17 and 75 nM. In animals, sumanirole elicits many physiological responses attributed to D(2)-like receptor function. In rats, sumanirole is a full agonist for elevation of striatal acetylcholine levels (ED(50) = 12.1 micromol/kg i.p.). Sumanirole s.c. dose dependently decreased plasma prolactin levels and depressed dopamine neuron firing rates in the substantia nigra pars compacta with an ED(50) of 2.3 micromol/kg i.v. This high selectivity for D(2) receptors translates into excellent locomotor stimulant activity in animal models of Parkinson's disease. In reserpinized, alpha-methyl-para-tyrosine-treated rats, sumanirole caused a significant and sustained increase in horizontal activity at doses > or =12.5 micromol/kg s.c. In unilateral 6-hydroxydopamine-lesioned rats, sumanirole caused profound, sustained rotational behavior and was substantially more efficacious than any other agonist tested. Sumanirole-stimulated rotational behavior was blocked by the dopamine receptor antagonist haloperidol. Sumanirole dose dependently improved disability scores and locomotor activities of two of three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In summary, sumanirole is the first published selective D(2) receptor agonist. The compound has activity in animal models of dopamine hypofunction and has a high level of efficacy in animal models of Parkinson's disease.

The effects of a selective dopamine D2 receptor agonist on behavioral and pathological outcome in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated squirrel monkeys.[Pubmed:15980058]

J Pharmacol Exp Ther. 2005 Sep;314(3):1257-66.

In this study, we investigated antiparkinsonian activity of the novel, highly selective dopamine D(2) receptor agonist sumanirole compared with two clinically effective dopaminergic therapies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. Squirrel monkeys were rendered parkinsonian by chronic administration of MPTP and subsequently dosed with vehicle, L-DOPA plus carbidopa (L-DOPA), ropinirole, or sumanirole over a duration of 8 weeks. Antiparkinsonian effects measured with a parkinsonian primate rating scale (PPRS) showed that sumanirole elicited improved functional outcome compared with vehicle. The dopamine D2/D3 agonist ropinirole improved behavioral outcome similar to sumanirole, whereas L-DOPA treatment yielded the most significant symptomatic improvement. The relative rank of therapies that elicited normalization of PPRS was L-DOPA > sumanirole; ropinirole did not normalize PPRS in any of the treated monkeys. Dyskinesias were present with L-DOPA treatment but were not observed in sumanirole-, ropinirole-, or placebo-treated primates. Pathologically, all MPTP-treated animals displayed neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and reactive astrocytosis. Neurons immunoreactive with antibodies to the nuclear transcription factor DeltaFosB were most significantly increased in the striatum of L-DOPA-treated monkeys. These results suggest that sumanirole can exert antiparkinsonian effects similar to L-DOPA without the behavioral and morphological consequences of the latter.

Sumanirole maleate (U-95666E; PNU-95666E) is a highly selective D2 receptor full agonist with an ED50 of about 46 nM. Sumanirole was developed for the treatment of Parkinson's disease and restless leg syndrome.

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