Clas Sonesson
University of Gothenburg
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Featured researches published by Clas Sonesson.
Clinical Neuropharmacology | 2010
Anders Lundin; Espen Dietrichs; Sara Haghighi; Marine-Louise Göller; Arvid Heiberg; Ghada Loutfi; Håkan Widner; Klas Wiktorin; Leif Wiklund; Anders Svenningsson; Clas Sonesson; Nicholas Waters; Susanna Waters; Joakim Tedroff
Objectives:To evaluate the efficacy and safety of the dopaminergic stabilizer pridopidine (ACR16) in patients with Huntingtons disease (HD). Methods:In a randomized, double-blind, placebo-controlled, 4-week trial, patients with HD received pridopidine (50 mg/d, n = 28) or placebo (n = 30). The primary outcome measure was the change from baseline in weighted cognitive score, assessed by cognitive tests (Symbol Digit Modalities, verbal fluency, and Stroop tests). Secondary outcome measures included changes in the Unified Huntingtons Disease Rating Scale, Hospital Anxiety and Depression Scale, Leeds Sleep Evaluation Questionnaire, Reitan Trail-Making Test A, and Clinical Global Impression of Change. Safety assessments were also performed. Results:There was no significant difference between pridopidine and placebo in the change from baseline of the weighted cognitive score. However, secondary measures such as affective symptoms showed trends toward improvement, and there was significant improvement in voluntary motor symptoms compared with placebo (P < 0.05). Pridopidine was well tolerated, with a safety profile similar to placebo. Conclusions:Pridopidine shows promise as a treatment for some of the symptoms of HD. In this small-scale study, the most notable effect was improvement in voluntary motor symptoms. Larger, longer-term trials are warranted.
European Journal of Pharmacology | 2010
Henrik Ponten; Johan Kullingsjö; Sören Lagerkvist; Peter R. Martin; Fredrik Pettersson; Clas Sonesson; Susanna Waters; Nicholas Waters
Pridopidine (ACR16) belongs to a new pharmacological class of agents affecting the central nervous system called dopaminergic stabilizers. Dopaminergic stabilizers act primarily at dopamine type 2 (D(2)) receptors and display state-dependent behavioural effects. This article aims to give an overview of the preclinical neurochemical and behavioural in vivo pharmacological properties of pridopidine. Pridopidine was given s.c. to male Sprague-Dawley rats (locomotor, microdialysis and tissue neurochemistry) and i.p. to Swiss male mice (tail suspension test). Pridopidine dose-dependently increased striatal tissue levels of the dopamine metabolite 3,4-dihydroxyphenylalanin (ED(50)=81 micromol/kg), and prefrontal cortex dialysate levels of dopamine and noradrenaline as measured by high performance liquid chromatography. The agent reduced hyperlocomotion (d-amphetamine: ED(50)=54 micromol/kg; MK-801: ED(50)=40 micromol/kg), but preserved spontaneous locomotor activity, confirming state-dependent behavioural effects. In addition, pridopidine significantly reduced immobility time in the tail suspension test. We conclude that pridopidine state-dependently stabilizes psychomotor activity by the dual actions of functional dopamine D(2) receptor antagonism and strengthening of cortical glutamate functions in various settings of perturbed neurotransmission. The putative restoration of function in cortico-subcortical circuitry by pridopidine is likely to make it useful for ameliorating several neurological and psychiatric disorders, including Huntingtons disease.
Synapse | 1998
Joakim Tedroff; Richard Torstenson; Per Hartvig; Clas Sonesson; Nicholas Waters; Arvid Carlsson; Henrik Neu; Karl-Johan Fasth; Bengt Långström
(−)‐OSU6162 is a substituted (S)‐3‐phenylpiperidine derivative which exhibits some affinity to the dopamine D2 receptor family. In vivo, the compound displays a unique normalizing profile on psychomotor activity by an intriguing mixture of stimulatory and inhibitory properties. In the present investigation, some of the effects of (−)‐OSU6162 on central dopaminergic function were studied by positron emission tomography (PET) and L‐[11C]DOPA in anaesthetized female rhesus monkeys. (−)‐OSU6162 displayed a dopaminergic tone‐dependent effect with a reduction in the striatal L‐[11C]DOPA influx rate in monkeys with high baseline values and an increased striatal L‐[11C]DOPA influx rate in animals with low baseline values. Infusion of (−)‐OSU6162 for a whole day resulted in a stable effect with no evidence of tolerance. (−)‐OSU6162 also stabilized dopaminergic function by attenuating the upregulation of the striatal L‐[11C]DOPA influx rate which has previously been shown to occur following 6R‐BH4 or 6R‐BH4 + L‐tyrosine infusions. This “Protean” effect of (−)‐OSU6162 on the striatal dopaminergic function corresponds to previous behavioral observations in intact animals and demonstrates a true functional correlation to the measures obtained with L‐[11C]DOPA and PET. The normalizing and stabilizing profile of (−)‐OSU6162 should be of value in treating a variety of disorders where an underlying dysregulation or disruption of dopaminergic function can be assumed. Synapse 28:280–287, 1998.
Progress in Neuro-psychopharmacology & Biological Psychiatry | 2004
Marie Nilsson; Arvid Carlsson; Katarina Rydén Markinhuhta; Clas Sonesson; Fredrik Pettersson; Maria Gullme; Maria Carlsson
The Carlsson research group has developed a series of compounds capable of stabilising the dopamine system without inducing the deleterious hypodopaminergia that encumbers the currently used antipsychotic drugs. In the present study one of these dopaminergic stabilisers, ACR16, was tested in a mouse model for cognitive deficits of schizophrenia and autism. Since we believe that hypoglutamatergia is a key element in both schizophrenia and autism we used mice rendered hypoglutamatergic by treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. MK-801 causes both hyperactivity and a behavioural primitivization. ACR16 attenuated the MK-801-induced hyperactivity and, in addition, caused a marked improvement of behavioural quality with a movement pattern approaching that of control animals. Since we believe that the impoverishment of the behavioural repertoire caused by MK-801 may correspond to the cognitive deficits seen in schizophrenia and autism, these results suggest that ACR16 may improve cognitive status in these disorders.
Neuropharmacology | 1999
Anna Ekesbo; Richard Torstenson; Per Hartvig; Arvid Carlsson; Clas Sonesson; Nicholas Waters; Joakim Tedroff; Bengt Långström
The substituted (S)-3-phenylpiperidine (-)-OSU6162 belongs to a novel class of functional modulators of dopaminergic systems. In vivo, (-)-OSU6162 has a unique stabilising profile on dopaminergic functions. In vitro this compound exhibits low affinity for the dopamine D2 receptor, but due to its similarity to neuroleptics on brain dopaminergic neurochemistry and different postsynaptic effects it has been characterised as a preferential dopamine autoreceptor antagonist. To further clarify the effects of (-)-OSU6162 on the postjunctional nigrostriatal dopaminergic system, dopamine receptor binding was measured in rhesus monkeys (Macaca mulatta) by positron emission tomography (PET) using the D1 and D2 dopamine receptor radioligands [11C]SCH23390 and [11C]raclopride respectively, before and during continuous intravenous infusions of(-)-OSU6162. Additionally, the test-retest variability of sequential [11C]SCH23390 scans was estimated. Following the administration of (-)-OSU6162, [11C]raclopride binding in striatum was dose-dependently decreased with a 76% reduction occurring after 3.0 mg/kg per h continuous infusion. Whereas (-)-OSU6162 in the lower doses had no effect on [11C]SCH23390 binding, the highest dose, 3.0 mg/kg per h, increased [11C]SCH23390 binding, which may indicate a potentiating effect on D1 dopamine receptor mediated functions. Thus, in contrast to the conditions in vitro, (-)-OSU6162 produces a high displacement of raclopride from D2 receptors in vivo.
Nuclear Medicine and Biology | 1997
Henrik Neu; Per Hartvig; Richard Torstenson; Karl Johan Fasth; Clas Sonesson; Nicholas Waters; Arvid Carlsson; Joakim Tedroff; Bengt Långström
The labelling of the presynaptic dopamine receptor antagonist (-)-OSU6162, ((S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine) was performed by an alkylation with [11C]methyl iodide of the thio anion (-)-OSU1281, followed by a selective oxidation to the corresponding methyl sulfone, [11C-methyl]-(-)-OSU6162. The total radiochemical yield calculated from the produced [11C]carbon dioxide to final product was about 25% and the time of synthesis was in the range of 40 min from end of bombardment. The synthesis of the precursor, (-)-OSU1281, was performed from (-)-3PPP in a three-step synthesis. The regional brain distribution of (-)-OSU6162 radiolabelled with 11C was studied in rhesus monkeys by means of positron emission tomography, PET. [11C-Methyl]-(-)-OSU6162 was rapidly and uniformly distributed to gray matters of the brain, and no decrease of radioactivity uptake in the brain was seen after pretreatment with 1 to 3 mg/kg/h of (-)-OSU6162. The effect of doses of 1 to 3 mg/kg/h of (-)-OSU6162 on the dopamine binding was studied by PET using [11C-methyl]raclopride. Radioactivity in the striatum was significantly and dose-dependently decreased by (-)-OSU6162 (r = 0.88), supporting competition with dopamine for selective binding to dopamine receptors.
Bioorganic & Medicinal Chemistry Letters | 1997
Clas Sonesson; Håkan Wikström; Martin W. Smith; Kjell Svensson; Arvid Carlsson; Nicholas Waters
Abstract A series of 3-arylpyrrolidines has been synthesised via palladium catalyzed arylation and evaluated for dopaminergic and serotonergic activity in vitro and in vivo. Compounds substituted by electron withdrawing groups on the meta position of the aromatic ring, were found to be preferential dopamine autoreceptor antagonists.
Journal of Medicinal Chemistry | 2012
Fredrik Pettersson; Peder Svensson; Susanna Waters; Nicholas Waters; Clas Sonesson
A series of para-substituted 4-phenylpiperidines/piperazines have been synthesized and their affinity to recombinant rat cerebral cortex monoamine oxidases A (MAO A) and B (MAO B) determined. Para-substituents with low dipole moment increased the affinity to MAO A, whereas groups with high dipole moment yielded compounds with no or weak affinity. In contrast, the properties affecting MAO B affinity were the polarity and bulk of the para-substituent, with large hydrophobic substituents producing compounds with high MAO B affinity. In addition, these compounds were tested in freely moving rats and the effect on the post-mortem neurochemistry was measured. A linear correlation was demonstrated between the affinity for MAO A, but not MAO B, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) in the striatum.
Bioorganic & Medicinal Chemistry Letters | 1994
Susanne R. Haadsma-Svensson; Martin W. Smith; Chiu-Hong Lin; J. Neil Duncan; Clas Sonesson; H»kan Wikström; Nicholas Waters; Arvid Carlsson; Kjell Svensson
Abstract A series of (+)-AJ76 and (+)-UH232 analogs with the C-5 methoxy group modified was synthesized and biologically evaluated. Compounds with a triflate or nitrile group were found to be behavioral stimulants with high metabolic stability. The triflate analogs also displayed a 14-fold preference for the D3 receptor site in vitro.
Journal of Medicinal Chemistry | 2012
Cecilia Mattsson; Theresa Andreasson; Nicholas Waters; Clas Sonesson
A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.