Kinetics, Brain Uptake, and Receptor Binding of Tandospirone and Its Metabolite l-(2-Pyrimidinyl)-piperazine

Lg, Miller; Ml, Thompson; Jj, Byrnes; Dj, Greenblatt; Shemer, Anne

doi:10.1097/00004714-199210000-00009

Cited by 27 publications

(8 citation statements)

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“…Furthermore, acute systemic administration of 5‐HT1A agonists increases noradrenaline (Barnes and Sharp,1999) and dopamine (Diaz‐Mataix et al,2005; Ichikawa et al,2001). Moreover, tandospirone is metabolized to 1‐(2‐pyrimidinyl)‐piperazine (1‐PP) in rodents and humans (Caccia et al,1982; Miller et al,1992), which acts as an antagonist at α2‐adrenoceptors (Newman‐Tancredi et al,1998; Tatarczynska et al,1989). Therefore, it is possible that recovery of lactate production by tandospirone is mediated by dopaminergic and/or noradrenalinergic activity.…”

Section: Discussionmentioning

confidence: 99%

Expression and regulation of the decoy bone morphogenetic protein receptor BAMBI in the developing avian face

Higashihori

Song

Richman

2008

Developmental Dynamics

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Here, we examine the expression and regulation of the gene BAMBI, a kinase-deficient decoy receptor capable of interacting with type I bone morphogenetic protein (BMP) receptors in avian embryos. Initially, expression was limited to the endoderm during neurula and pharyngula stages. From embryonic day 3.5 (stage 20) and onward, BAMBI expression almost perfectly overlapped with known expression patterns for BMP4, particularly in the face and limbs. We performed bead implant experiments in the face to see which signals could be repressing or promoting expression of BAMBI. Our data point to retinoids and BMPs as being major positive regulators of BAMBI expression; however, fibroblast growth factor 2 acts to repress BAMBI. Furthermore, retinoic acid is likely to act directly on BAMBI as induction occurs in the presence of cycloheximide. The data suggested that BAMBI could be used to regulate Bmp signaling during tissue interactions that are an integral part of facial morphogenesis. Developmental Dynamics 237:1500 -1508, 2008.

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Section: Discussionmentioning

confidence: 99%

Expression and regulation of the decoy bone morphogenetic protein receptor BAMBI in the developing avian face

Higashihori

Song

Richman

2008

Developmental Dynamics

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“…The inconsistency with the results for tandospirone may be due to its major metabolite, 1-(2-pyrimidinyl) piperazine (1-PP). After oral administration tandospirone is rapidly metabolized to 1-PP, and 1-PP has low affinity to the 5-HT 1A receptors but has high affinity to the ␣ 2 -adrenoceptors (Miller et al, 1992). Because TZB-30878 does not possess the 1-PP structure, the effects of TZB-30878 are unrelated to 1-PP.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Properties of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a Novel Therapeutic Agent for Diarrhea-Predominant Irritable Bowel Syndrome (IBS) and Its Effects on an Experimental IBS Model

Tamaoki¹,

Yamauchi²,

Nakano³

et al. 2007

J Pharmacol Exp Ther

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3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878) is a novel compound with both 5-hydroxytryptamine (5-HT) 1A agonism and 5-HT 3 antagonism effects. We hypothesized that TZB-30878 might have benefits from these dual effects as a medication for diarrhea-predominant irritable bowel syndrome (d-IBS), and these studies were designed to confirm the pharmacological properties of TZB-30878 and its efficacy in an IBS-like animal model. The binding assays demonstrated that [ 3 H]TZB-30878 selectively binds to human 5-HT 1A and 5-HT 3 receptors, with K d values of 0.68 Ϯ 0.03 and 8.90 Ϯ 1.73 nM, respectively. Systemic administration of TZB-30878 inhibited 5-HT-induced bradycardia in a dose-dependent manner in rats. In behavioral assays TZB-30878 produced signs of 5-HT syndrome in rats. These results suggest that TZB-30878 has dual effects as a 5-HT 1A receptor agonist and a 5-HT 3 receptor antagonist. Finally, we evaluated the effects of TZB-30878 on wrap restraint stress-induced defecation in an IBS-like model in rats. TZB-30878 (1-10 mg/kg p.o.) normalized stress-induced defecation in a dose-dependent manner, whereas the 5-HT 1A agonist tandospirone (30 and 100 mg/kg p.o.) and the 5-HT 3 antagonist alosetron (1-10 mg/kg p.o.) did not show such effects. Furthermore, this efficacy of TZB-30878 was partly antagonized by a 5-HT 1A antagonist, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635). These results suggest that 5-HT 1A receptor agonism and 5-HT 3 receptor antagonism contribute to the efficacy of TZB-30878 in the IBS-like model. The efficacy of TZB-30878 supports the concept that the presence of both actions, namely 5-HT 1A receptor agonism and 5-HT 3 receptor antagonism, could be an important mechanism in the treatment of d-IBS.

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“…The authors conducted a series of pilot studies 47,48,51 on the effects of the addition of tandospirone, a 5-HT 1A partial agonist and azapirone derivative, 71,72 to ongoing treatment with small to moderate doses of typical antipsychotic drugs (mainly haloperidol), on cognitive function in patients with schizophrenia. 47,48,51 The addition of tandospirone (30 mg/day), but not placebo, to typical antipsychotic drugs for 4 to 6 weeks, was found to improve executive function in one study 47 and verbal learning and memory in others 47,48,51 (Figure 7).…”

Section: Effect Of Tandospirone On Cognitive Function In Schizophreniamentioning

confidence: 99%

Serotonin1A receptors in the pathophysiology of schizophrenia: development of novel cognition-enhancing therapeutics

Sumiyoshi

Bubeníková-Valešová²,

Horáček³

et al. 2008

Adv Therapy

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Serotonin (5-HT) receptors have been suggested to play key roles in psychosis, cognition, and mood via influence on neurotransmitters, synaptic integrity, and neural plasticity. Specifically, genetic evidence indicates that 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor single-nucleotide polymorphisms (SNPs) are related to psychotic symptoms, cognitive disturbances, and treatment response in schizophrenia. Data from animal research suggest the role of 5-HT in cognition via its influence on dopaminergic, cholinergic, glutamatergic, and GABAergic function. This article provides up-to-date findings on the role of 5-HT receptors in endophenotypic variations in schizophrenia and the development of newer cognition-enhancing medications, based on basic science and clinical evidence. Imaging genetics studies on associations of polymorphisms of several 5-HT receptor subtypes with brain structure, function, and metabolism suggest a role for the prefrontal cortex and the parahippocampal gyrus in cognitive impairments of schizophrenia. Data from animal experiments to determine the effect of agonists/antagonists at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors on behavioral performance in animal models of schizophrenia based on the glutamatergic hypothesis provide useful information. For this purpose, standard as well as novel cognitive tasks provide a measure of memory/information processing and social interaction. In order to scrutinize mixed evidence for the ability of 5-HT(1A) agonists/antagonists to improve cognition, behavioral data in various paradigms from transgenic mice overexpressing 5-HT(1A) receptors provide valuable insights. Clinical trials reporting the advantage of 5-HT(1A) partial agonists add to efforts to shape pharmacologic perspectives concerning cognitive enhancement in schizophrenia by developing novel compounds acting on 5-HT receptors. Overall, these lines of evidence from translational research will facilitate the development of newer pharmacologic strategies for the treatment of cognitive disturbances of schizophrenia.

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Kinetics, Brain Uptake, and Receptor Binding of Tandospirone and Its Metabolite l-(2-Pyrimidinyl)-piperazine

Cited by 27 publications

References 0 publications

Expression and regulation of the decoy bone morphogenetic protein receptor BAMBI in the developing avian face

Expression and regulation of the decoy bone morphogenetic protein receptor BAMBI in the developing avian face

Pharmacological Properties of 3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a Novel Therapeutic Agent for Diarrhea-Predominant Irritable Bowel Syndrome (IBS) and Its Effects on an Experimental IBS Model

Serotonin1A receptors in the pathophysiology of schizophrenia: development of novel cognition-enhancing therapeutics

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