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| 2. |
- Burstein, ES, et al.
(författare)
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II. In vitro evidence that (-)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors
- 2011
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Ingår i: JOURNAL OF NEURAL TRANSMISSION. - 0300-9564. ; 118:11, s. 1523-1533
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: (-)-OSU6162 has promise for treating Parkinson's disease, Huntington's disease and schizophrenia. Behavioral tests evaluating the locomotor effects of (-) and (+)-OSU6162 on 'low activity' animals (reserpinized mice and habituated rats) and 'high activity' animals (drug naive mice and non-habituated rats) revealed that both enantiomers of OSU6162 had dual effects on behavior, stimulating locomotor activity in 'low activity' animals and inhibiting locomotor activity in 'high activity' animals. To elucidate a plausible mechanism of action for their behavioral effects, we evaluated the intrinsic actions of (-)- and (+)-OSU6162, and a collection of other antipsychotic and antiparkinsonian agents at 5-HT2A and D2 receptors in functional assays with various degrees of receptor reserve, including cellular proliferation, phosphatidyl inositol hydrolysis, GTP gamma S and beta-arrestin recruitment assays. We also tested for possible allosteric actions of (-)-OSU6162 at D2 receptors. Both enantiomers of OSU6162 were medium intrinsic activity partial agonists at 5-HT2A receptors and low intrinsic activity partial agonists at D2 receptors. (+)-OSU6162 had higher efficacy at 5-HT2A receptors, which correlated with its greater stimulatory activity in vivo, but (-)-OSU6162 had higher potency at D2 receptors, which correlated with its greater inhibitory activity in vivo. (-)-OSU6162 did not display any convincing allosteric properties. Both (+)- and (-)-OSU6162 were significantly less active at 27 other monoaminergic receptors and reuptake transporters tested suggesting that D2 and 5-HT2A receptors play crucial roles in mediating their behavioral effects. Compounds with balanced effects on these two receptor systems may offer promise for treating neuropsychiatric diseases.
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- Johansson, Birgitta, 1957, et al.
(författare)
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Placebo-controlled cross-over study of the monoaminergic stabiliser (-)-OSU6162 in mental fatigue following stroke or traumatic brain injury
- 2012
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press (CUP). - 0924-2708 .- 1601-5215. ; 24:5, s. 266-274
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Tidskriftsartikel (refereegranskat)abstract
- Objective Mental fatigue occurring after a stroke or traumatic brain injury (TBI) often results in difficulties returning to work and pursuing social activities. No effective treatment of this condition is available today. In this study, we have tested a novel pharmacological strategy using the monoaminergic stabiliser (-)-OSU6162. Methods (-)-OSU6162 was given orally for 4 weeks in doses increasing from 15 to 45 mg b.i.d. to 12 patients suffering from mental fatigue, following upon stroke (n?=?6) or TBI (n?=?6). (-)-OSU6162 was compared with placebo using a double-blind, randomised cross-over design. Patients included were well rehabilitated physically with no gross impairment in cognitive functions other than those related to the mental fatigue. Results (-)-OSU6162 caused a remarkable improvement in mental stamina, as evaluated by a self-assessment scale on mental fatigue. Statistical significance was reached on the primary endpoint (Mental Fatigue Scale). There was a trend towards improvement in the secondary endpoints processing speed and attention. Principal component analysis showed an overall positive treatment effect in 7 of 12 patients. Beneficial responses were seen already during the first few days of active drug treatment. Increasing dosage caused no further improvement. Adverse reactions consisted of short-lasting mild nausea and attenuated appetite. These side effects disappeared upon dose reduction. Conclusion The monoaminergic stabiliser (-)-OSU6162 offers promise as a candidate for treatment of mental fatigue after a stroke or TBI.
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| 5. |
- Kloberg, A., et al.
(författare)
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Tolerability and efficacy of the monoaminergic stabilizer (-)-OSU6162 (PNU-96391A) in Huntington's disease: A double-blind cross-over study
- 2014
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press. - 0924-2708 .- 1601-5215. ; 26:5, s. 298-306
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the safety (primary objective) and efficacy (secondary objective) of (-)-OSU6162 in Huntington's disease (HD). Methods In a double-blind, cross-over trial, patients with HD were randomly assigned to start treatment on either (-)-OSU6162 or placebo. After 4 weeks, those patients who initially received active drug were switched to placebo for another 4 weeks, and vice versa. During the first week the (-)-OSU6162 dose was 15 mg twice daily, during the second week 30 mg twice daily, and during the last 2 weeks 45 mg twice daily. Motor, cognitive, mental and social functions were rated by the clinical investigator or by self-assessment, using established rating scales. Results Fifteen patients fulfilling inclusion and exclusion criteria completed the study. (-)-OSU6162 was well tolerated by all patients and no adverse effects were observed. (-)-OSU6162 treatment significantly improved the Short Form 36 Vitality score, mainly due to an improvement of the individual item 'worn-out' (VT3). In addition, an improvement of depressive symptoms was found using Beck Depression Inventory. In contrast to a general trend of improvement in several non-motor variables only small and non-significant differences between (-)-OSU6162 and placebo were found regarding motor functions. Conclusions (-)-OSU6162 offers promise for the treatment of HD, as a drug with good tolerability, capable of improving the patients' experienced non-motor functions such as energy and mood and thus alleviating symptoms of great importance for their quality of life. © © Scandinavian College of Neuropsychopharmacology 2014.
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- Rung, Johan P., 1973, et al.
(författare)
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Effects of the dopamine stabilizers (S)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats.
- 2011
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Ingår i: Naunyn-Schmiedeberg's archives of pharmacology. - : Springer Science and Business Media LLC. - 1432-1912 .- 0028-1298.
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Tidskriftsartikel (refereegranskat)abstract
- Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.
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| 7. |
- Nilsson, Marie, 1968, et al.
(författare)
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The monoaminergic stabilizer (-)-OSU6162 reverses delay-dependent natural forgetting and improves memory impairment induced by scopolamine in mice
- 2013
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 75, s. 399-406
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to evaluate the effect of the monoaminergic stabilizer (-)-OSU6162 on spatial recognition memory. Male NMRI mice were tested in the object location model which is based on the animals’ inherent interest to examine changes in their environment: The animals’ propensity to explore relocated objects in relation to unaltered objects, presented in two different sessions (sample and trial), was studied. In a first series of experiments the effect of (-)-OSU6162 on natural forgetting was evaluated. With an inter-session interval (ISI) of 30 min or an hour, untreated mice spent longer time exploring the displaced object, but when the time between sessions was as long as 6 h, the mice did not identify the displaced object. However, using the 6 h ISI design we found that (-)-OSU6162 in doses up to 30 mmol/kg, given directly after the sample session, caused an increased interest for the displaced object. Twenty-four hours after administration, (-)-OSU6162 was still effective in facilitating identification of the displaced object. We also evaluated the effect of (-)-OSU6162 on scopolamine-induced memory deficits in this model e the two agents were given 30 min before the sample session and the ISI was one hour. Under these conditions scopolamine induced a deficit in object location memory and this effect was counteracted by (-)-OSU6162. The data from the present study suggest that (-)-OSU6162 prolongs object location memory in normal mice and reverses scopolamine-induced memory deficits. (-)-OSU6162 might be a valuable drug candidate for memory deficits and other cognitive impairments.
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