Isolation and structure of a hoplonemertine toxin

Kem, William R.; Abbott, B. C.; Coates, Robert M.

doi:10.1016/0041-0101(71)90039-0

Cited by 87 publications

(40 citation statements)

References 6 publications

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“…This is one of a series of compounds derived from anabaseine, an alkaloid found in marine worms [82,83]. DMXBA is a partial agonist at the α7 nicotinic cholinergic receptor [84,85] and a weak competitive antagonist at the α4ß2 nicotinic cholinergic receptors and 5HT 3 receptors [86,87].…”

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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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: 99%

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

Olincy

Stevens

2007

Biochemical Pharmacology

125

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“…2), an alkaloid whose synthesis (Spath and Mamoli, 1936) was reported the same year that Bacq first published his discovery of nemertine toxins. To identify unequivocally the nemertine toxin anabaseine was synthesized according to their method and found to be biologically as well as chemically identical with the natural toxin (Kem et al, 1971). Small samples of several other nemertine species were also available for analysis.…”

Section: Paranemertes Toxinmentioning

confidence: 99%

“…This bipyridyl was inactive upon vertebrate nicotinic receptors. Either the crustacean nicotinic receptor mediating the toxic response does not require a cationic ligand, or alternately, the bipyridyl is acting through a different receptor (Kem, 1971;1973;Kern et al, 1976).…”

Section: Pharmacological Actions Of Anabaseinementioning

confidence: 99%

Alzheimer's drug design based upon an invertebrate toxin (anabaseine) which is a potent nicotinic receptor agonist

Kem

1997

Invertebrate Neuroscience

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Naturally occurring toxins can often serve as useful chemical tools for investigating signalling processes in nervous and other systems. Tetrodotoxin and alpha-bungarotoxin are prime examples of toxins which are widely used in neurobiological research. Some toxins may also become molecular models for designing new drugs. Usually drugs are small, non-peptide molecules, as these display better bioavailability, longer durations of action and are less likely to generate immune responses. The relatively large size and conformational flexibility of peptides and protein toxins makes them more challenging molecular models for rational drug design. This article considers a marine invertebrate toxin, anabaseine, and describes how manipulation of the structure of this alkaloid has provided a drug candidate which selectively stimulates mammalian brain alpha7 nicotinic receptors. Numerous anabaseine analogs were synthesized and subjected to a variety of pharmacological, behavioral and toxcicological tests. This led to the choice of GTS-21 (also known as 3-(2,4-dimethoxybenzylidene)-anabaseine or DMXBA), as a drug candidate for the treatment of Alzheimer's dementia. The chemical and pharmacological properties of GTS-21 are compared with those of the initial lead compound, anabaseine.

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“…By using a very low-dosage level of mecamylamine in young rabbits so that nicotinic cholinergic receptors would be selectively inhibited, we demonstrated a role for nicotinic cholinergic receptors in eyeblink conditioning because the acquisition of CRs was severely disrupted (15). A synthesized analog of the marine natural product anabasine (16) called GTS-21 [3-(2,4-dimethoxybenzylidene)anabaseine] has been found to preferentially interact with ␣7 neuronal nicotinic receptors. Several doses of GTS-21 were administered to older rabbits, and this drug enabled older animals to produce significantly more CRs than did vehicle-treated older rabbits (17).…”

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confidence: 99%

Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning

Woodruff-Pak¹

2001

Proceedings of the National Academy of Sciences

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Classical eyeblink conditioning is a well-characterized model paradigm that engages the septohippocampal cholinergic system. This form of associative learning is impaired in normal aging and severely disrupted in Alzheimer's disease (AD). Some nicotinic cholinergic receptor subtypes are lost in AD, making the use of nicotinic allosterically potentiating ligands a promising therapeutic strategy. The allosterically potentiating ligand galantamine (Gal) modulates nicotinic cholinergic receptors to increase acetylcholine release as well as acting as an acetylcholinesterase (AChE) inhibitor. Gal was tested in two preclinical experiments. In Experiment 1 with 16 young and 16 older rabbits, Gal (3.0 mg͞kg) was administered for 15 days during conditioning, and the drug significantly improved learning, reduced AChE levels, and increased nicotinic receptor binding. In Experiment 2, 53 retired breeder rabbits were tested over a 15-wk period in four conditions. Groups of rabbits received 0.0 (vehicle), 1.0, or 3.0 mg͞kg Gal for the entire 15-wk period or 3.0 mg͞kg Gal for 15 days and vehicle for the remainder of the experiment. Fifteen daily conditioning sessions and subsequent retention and relearning assessments were spaced at 1-month intervals. The dose of 3.0 mg͞kg Gal ameliorated learning deficits significantly during acquisition and retention in the group receiving 3.0 mg͞kg Gal continuously. Nicotinic receptor binding was significantly increased in rabbits treated for 15 days with 3.0 mg͞kg Gal, and all Gal-treated rabbits had lower levels of brain AChE. The efficacy of Gal in a learning paradigm severely impaired in AD is consistent with outcomes in clinical studies.

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Isolation and structure of a hoplonemertine toxin

Cited by 87 publications

References 6 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

Alzheimer's drug design based upon an invertebrate toxin (anabaseine) which is a potent nicotinic receptor agonist

Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning

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