Effects of the substituted (S)-3-phenylpiperidine (?)-OSU6162 on PET measurements in subhuman primates: Evidence for tone-dependent normalization of striatal dopaminergic activity

Tedroff, Joakim; Torstenson, Richard; Hartvig, Per; Sonesson, Clas; Waters, Nicholas; Carlsson, Arvid; Neu, Henrik; Fasth, KJ; Långström, Bengt

doi:10.1002/(sici)1098-2396(199804)28:4<280::aid-syn3>3.0.co;2-5

Cited by 42 publications

(14 citation statements)

References 34 publications

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“…It has a preference for dopamine D2 autoreceptors, producing weak behavioral activity when baseline activity is low and counteracting behavior stimulation in animals 9 . Thus, the drug is said to exhibit baseline‐dependent behavioral and neurochemical normalization, including activation at low dopaminergic tone and inhibition at high dopaminergic tone 10 . These unique dopamine‐modulating effects of PNU‐96391 make it valuable in the treatment of motor complications resulting from the administration of levodopa in patients with Parkinson's disease and other movement disorders 11,12 …”

Section: Discussionmentioning

confidence: 99%

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Single Oral Dose Safety, Tolerability, and Pharmacokinetics of PNU‐96391 in Healthy Volunteers

Rodríguez

Azie²,

Adams³

et al. 2004

The Journal of Clinical Pharma

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The safety, tolerability, and pharmacokinetics of PNU-96391, an orally active weak dopamine D2 receptor antagonist with modulatory properties of central dopaminergic function, was characterized. Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebo-controlled, single-dose study. Subjects were assigned to single oral doses of placebo and 1, 3, 10, 30, 100, 150, and 200 mg PNU-96391. Safety and tolerability were assessed using telemetry, Holter monitoring, surface ECG, vital signs, safety laboratories, and adverse event reports. Pharmacokinetic parameters were determined by model-independent techniques. Adverse events were infrequent, of mild to moderate intensity, and in the dose range of 1 to 150 mg. Dose escalation was stopped at 200 mg because of severe nausea, dizziness, lightheadedness, and tachycardia. Besides the increase in heart rate, no other drug-related effects on vital signs were observed. Safety laboratory measurements were not significantly changed. Evidence of drug activity was demonstrated by a dose-dependent elevation in serum prolactin. PNU-96391 was rapidly absorbed, with maximum concentrations achieved between 0.5 and 4 hours in all subjects. The half-life of the drug was short (2 to 6 h). The main metabolite, PNU-100014, was rapidly formed, with a t(max) ranging from 1 to 6 hours. Peak levels of the metabolite are approximately half of the parent drug, and the half-life is slightly longer (4 to 10 h). Increases in dose resulted in linear increases in exposure for both PNU-96391 and PNU-100014. Hence, PNU-96391 was well tolerated at doses ranging from 1 to 150 mg.

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Section: Discussionmentioning

confidence: 99%

“…Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebocontrolled, single-dose study. Subjects were assigned to single oral doses of placebo and 1,3,10, 30, 100, 150,. Safety and tolerability were assessed using telemetry, Holter monitoring, surface ECG, vital signs, safety laboratories, and adverse event reports.…”

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confidence: 99%

Single Oral Dose Safety, Tolerability, and Pharmacokinetics of PNU‐96391 in Healthy Volunteers

Rodríguez

Azie²,

Adams³

et al. 2004

The Journal of Clinical Pharma

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“…It is heuristically less interesting because it has higher affinity for the D 3 and D 4 receptors, and weak partial agonist activity at D 2 receptors [149]. Other compounds of potential interest include UH232 [23, 150], S32504 [151], SDZ 208-912 [152, 153], PD 143188 (CI-1007) [154], SLV-308 (SME-308) [155, 156], F15063 [157, 158], SSR181507 [159], (-)-OSU6162 (PNU-96391A; Figure 5) [160, 161], ACR16 [162, 163], and many others. What is of particular importance is that there has been the view that dopamine stabilization (i.e., the unique clinical effects of aripiprazole) can be explained simply “partial agonist intrinsic activity.” Thus, Tadori et al [164] compared aripiprazole, bifeprunox, SDZ 208-912, OPC-4392, and ACR16 in terms of degrees of intrinsic activity (i.e., inhibition of forskolinstimulated cAMP accumulation) in clonal CHO cell lines expressing high and low densities of human dopamine D 2L and D 2S receptors.…”

Section: Impact Of Functional Selectivity and Research Issues For mentioning

confidence: 99%

Third Generation Antipsychotic Drugs: Partial Agonism or Receptor Functional Selectivity?

Mailman¹,

Murthy²

2010

CPD

264

194

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Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D 2 receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D 2 and 5-HT 2A antagonists, and those that also bind with modest affinity to D 2 , 5-HT 2A , and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D 2 partial agonism or D 2 functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D 2 functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D 2 antagonists.Keywords functional selectivity; antipsychotic drugs; schizophrenia; receptor mechanisms; G protein-coupled receptors; dopamine receptors; serotonin receptors; drug action A. The first two generations of antipsychotic drugsThe serendipitous observations about antipsychotic actions of chlorpromazine [1] ultimately led to the finding that these antipsychotic effects were due to antidopaminergic actions [2]. Numerous antipsychotics were subsequently developed that, like chlorpromazine, work primarily as dopamine D 2 receptor antagonists. Drugs of this type (first called typical and now named first generation antipsychotics) include a variety of different chemical classes. These NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Curr Pharm Des. 2010 ; 16(5): 488-501. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript typical drugs can be classified as high, intermediate, or low potency based on their average daily dose range, with their clinical potency often highly correlated with their affinity for the dopamine D 2 receptor [3]. Thus, actions at dopamine systems have been a critical mechanism in all currently approved antipsychotic drugs and many of the compounds in the discovery and development pipeline. Dopamine systems and their rece...

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“…While clinical results are consistent, the proposed mechanism of action of pridopidine is not fully understood . The term “dopamine stabilizer” was derived from behavioral experiments in animals that carried a pharmacologically induced brain lesion: in this setting pridopidine was thought to enhance locomotor activity under conditions of low dopaminergic tone and decrease activity when dopamine signaling was high . It was suggested, that dopamine stabilizers act primarily at dopamine type 2 (D2) receptors and display state‐dependent behavioral effects .…”

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confidence: 99%

“…9 The term "dopamine stabilizer" was derived from behavioral experiments in animals that carried a pharmacologically induced brain lesion: in this setting pridopidine was thought to enhance locomotor activity under conditions of low dopaminergic tone and decrease activity when dopamine signaling was high. [10][11][12][13] It was suggested, that dopamine stabilizers act primarily at dopamine type 2 (D2) receptors 9,14,15 and display state-dependent behavioral effects. 10 However, it could clinically be challenged why modulation of D2-receptor activity does not translate into changes in chorea scores; neuroleptics such as tiapride are D2receptor antagonists and known to reduce chorea.…”

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confidence: 99%

The pridopidine paradox in Huntington's disease

Reilmann¹

2013

Movement Disorders

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Effects of the substituted (S)-3-phenylpiperidine (?)-OSU6162 on PET measurements in subhuman primates: Evidence for tone-dependent normalization of striatal dopaminergic activity

Cited by 42 publications

References 34 publications

Single Oral Dose Safety, Tolerability, and Pharmacokinetics of PNU‐96391 in Healthy Volunteers

Single Oral Dose Safety, Tolerability, and Pharmacokinetics of PNU‐96391 in Healthy Volunteers

Third Generation Antipsychotic Drugs: Partial Agonism or Receptor Functional Selectivity?

The pridopidine paradox in Huntington's disease

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