Safety, Pharmacokinetics, and Effects on Cognitive Function of Multiple Doses of GTS-21 in Healthy, Male Volunteers

Kitagawa, Harumi; Takenouchi, Toshiharu; Azuma, Ryotaro; Wesnes, Keith; Kramer, William G.; Clody, Donald E.; Burnett, Angela L

doi:10.1038/sj.npp.1300028

Cited by 221 publications

(174 citation statements)

References 15 publications

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“…Additionally, DMXBA improved subject performance speed on numeric and spatial working memory task. Improvement was generally seen with the 25 mg dose, with further improvement at the 75 mg dose and an equivalent effect at the 150 mg dose [118].…”

Section: Dmxba As a Prototype Drugmentioning

confidence: 87%

“…The first stage in human testing with DMXBA was to initially administer this compound to normal male subjects to assess for safety, tolerability, pharmacokinetics and possible effects on cognition prior to its study as a cognitive enhancer in Alzheimer's disease [118]. Subjects were randomized to DMXBA (25, 75 and 150 mg) or placebo administered three times daily for 5 days with a 10 day washout period between drug-taking periods.…”

Section: Dmxba As a Prototype Drugmentioning

confidence: 99%

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Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Olincy

Stevens

2007

Biochemical Pharmacology

125

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Current antipsychotic treatments fail to fully address the range of symptoms of schizophrenia, particularly with respect to social and occupational dysfunctions. Recent work has highlighted the role of nicotinic in both cognitive and attentional deficits as well as deficient processing of repetitive sensory information. The predilection for schizophrenia patients to be extremely heavy cigarette smokers may be related to their attempt to compensate for a reduction in hippocampal α7 nicotinic cholinergic receptors by delivering exogenous ligand to the remaining receptors. Studies in rodent models of both learning and memory deficits and deficits in sensory inhibition have confirmed a role for α7 subtype of the nicotinic cholinergic receptors in these processes. Rodent studies also demonstrated the efficacy of a selective partial α7 nicotinic agonist, DMXBA, to improve these deficits. Subsequent human clinical trials demonstrated improved sensory inhibition in 12 schizophrenia patients and showed improvement in several subtests of the RBANS learning and memory assessment instrument. These data suggest that therapeutic agents selected for α7 nicotinic activity may have utility in treating certain symptoms of schizophrenia. KeywordsSchizophrenia; nicotinic receptors; DMXBA; P50 auditory evoked potential; cognitive deficits; nicotine Although the positive symptoms such as hallucinations and delusions of schizophrenia are partially treated with the available antipsychotic medications, social and occupational dysfunction remains a major issue in treating this disorder. Cognitive deficits have been identified as more closely related to ability to adequately function [1]. In the search for new and more effective therapeutic agents for schizophrenia, recent attention has turned the nicotinic cholinergic receptors system. α7 and P50 Auditory GatingPeople with schizophrenia, in addition to the cardinal symptoms of hallucinations and delusions, suffer from the inability to focus attention. This may stem from being overwhelmed

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Section: Dmxba As a Prototype Drugmentioning

confidence: 87%

Section: Dmxba As a Prototype Drugmentioning

confidence: 99%

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Olincy

Stevens

2007

Biochemical Pharmacology

125

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“…One of the most characteristic alpha7nAChR-agonist is GTS21. GTS21 (3-[(2,4-dimethoxy) benzylidene]-anabaseine), a partial alpha7nAChR-agonist, enhances attention, working memory and episodic memory measured in healthy humans (Kitagawa et al, 2003). This compound was well tolerated at doses of up 450 mg/day, doses higher than those allowed by nicotine, and no significant side effects were observed.…”

Section: Alpha7nachr-agonists and Allosteric Modulators In Neurodegenmentioning

confidence: 99%

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

Conejero-Goldberg

Davies

Ulloa

2008

Neuroscience & Biobehavioral Reviews

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Alzheimer's disease (AD) is the leading cause of dementia affecting over 25 million people worldwide. Classical studies focused on the description and characterization of the pathological hallmarks found in AD patients including the neurofibrillary tangles and the amyloid plaques. Current strategies focus on the etiology of these hallmarks and the different mechanisms contributing to neurodegeneration. Among them, recent studies reveal the close interplay between the immunological and the neurodegenerative processes. This article examines the implications of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) as a critical link between inflammation and neurodegeneration in AD. Alpha7nAChRs are not only expressed in neurons but also in Glia cells where they can modulate the immunological responses contributing to AD. Successful therapeutic strategies against AD should consider the connections between inflammation and neurodegeneration. Among them, alpha7nAChR may represent a pharmacological target to control these two mechanisms during the pathogenesis of neurodegenerative and behavioral disorders.

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“…GTS-21 has been shown to display memory-enhancing properties in passive and active avoidance tests, in the Morris and radial mazes in rats (Arendash et al, 1995;Meyer et al, 1998;Kem, 2000). It has even proven to have favorable effects on cognitive function in humans (Kitagawa et al, 2003) especially on attention, working memory, and episodic secondary memory. However, this compound is not selective for the human a7 n-AChR, as it is also functionally active at a4b2 n-AChR (Briggs et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

Pichat

Bergis

Terranova

et al. 2006

Neuropsychopharmacol

235

155

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SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective a7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the a7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801-or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective a7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.

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Safety, Pharmacokinetics, and Effects on Cognitive Function of Multiple Doses of GTS-21 in Healthy, Male Volunteers

Cited by 221 publications

References 15 publications

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

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