Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00176.X
S. Strittmatter
{"title":"CNS Axon Regeneration and Nogo","authors":"S. Strittmatter","doi":"10.1111/J.1527-3458.2000.TB00176.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00176.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"11 1","pages":"32-32"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87181712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2004.TB00018.X
Y. Yamaguchi, M. Takano, K. Saitoh, T. Matsuno, S. Kawashima
{"title":"Effects of Azaindolizindone Derivatives ZSET845 and ZSET1446 on Acetylcholine Release in the Cortex and Learning Impairments in the Rat","authors":"Y. Yamaguchi, M. Takano, K. Saitoh, T. Matsuno, S. Kawashima","doi":"10.1111/J.1527-3458.2004.TB00018.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2004.TB00018.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"52 1","pages":"196-196"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73073420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00154.X
A. Demuro, R. Miledi
Pitrazepin [3-(piperazinyl-1)-9H-dibenz(c.f)triazolo(4,5-a)azepin], is an N-aryl-piperazine derivative, whose heterocyclic structure is similar to that of atypical antipsychotics like clozapine. This paper is an overview of the pharmacological actions of pitrazepin, with an emphasis on its actions on GABAA and glycine neurotransmitter receptors. Recent results on the antagonist actions of pitrazepin on acetylcholine (ACh) currents in oocytes expressing either rat neuronal or mouse muscle nicotinic acetylcholine receptors are presented. Many of the pharmacological features of the new-generation antipsychotics have been derived from studies of structurally treated drugs. A detailed understanding of the ineractions of these drugs with neurotransmitter receptor is necessary to develop more effective antipsychotics.
{"title":"Pitrazepin: Interactions with Transmitter Receptors of the Central and Peripheral Nervous Systems","authors":"A. Demuro, R. Miledi","doi":"10.1111/J.1527-3458.2000.TB00154.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00154.X","url":null,"abstract":"Pitrazepin [3-(piperazinyl-1)-9H-dibenz(c.f)triazolo(4,5-a)azepin], is an N-aryl-piperazine derivative, whose heterocyclic structure is similar to that of atypical antipsychotics like clozapine. This paper is an overview of the pharmacological actions of pitrazepin, with an emphasis on its actions on GABAA and glycine neurotransmitter receptors. Recent results on the antagonist actions of pitrazepin on acetylcholine (ACh) currents in oocytes expressing either rat neuronal or mouse muscle nicotinic acetylcholine receptors are presented. Many of the pharmacological features of the new-generation antipsychotics have been derived from studies of structurally treated drugs. A detailed understanding of the ineractions of these drugs with neurotransmitter receptor is necessary to develop more effective antipsychotics.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"25 1","pages":"290-302"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79098932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00174.X
A. Horwich
{"title":"Role of Chaperones in Neurodegeneration","authors":"A. Horwich","doi":"10.1111/J.1527-3458.2000.TB00174.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00174.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"27 1","pages":"29-29"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80231262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00155.X
G. Tollefson, C. C. Taylor
The novel antipsychotic agent olanzapine (Zyprexa, Eli Lilly and Company) is a thienobenzodiazepine analog marketed for the treatment of schizophrenia. Olanzapine's diverse receptor binding profile and greater affinity for serotonin receptors over dopamine receptors is thought to impart antipsychotic efficacy with a low incidence of serious extrapyramidal symptoms (EPS). With once daily dosing steady-state plasma concentrations reached within approximately 1 week. Olanzapine is extensively metabolized by the liver, is mostly excreted in the urine, and has few drug intractions. In clinical trials, the efficacy of olanzapine for treating schizophrenia is better than placebo and haloperidol and comparable to risperidone. Olanzapine may also ameliorate some comorbid symptoms including negative symptoms, depression, anxiety, substance abuse, and cognitive dysfunction, and it is effective in the long-term maintenance of response, treatment-resistance, and improving quality of life. The overall direct costs are lower with olanzapine treatment compared with haloperidol or risperidone treatment. In clinical trials, olanzapine demonstrates a favorable safety profile. The most frequently reported treatment-emergent adverse events are somnolence, schizophrenic reaction, insomnia, headache, agitation, rhinitis, and weight gain. Significantly fewer EPS (based on formal rating scales) and incidences of tardive dyskinesia have been reported for olanzapine compared with haloperidol. Olanzapine has not been associated with persistent elevations of prolactin above the upper limit of normal nor has it been associated with clinically significant changes in cardiac QTc interval. Fewer incidences of suicide attempts have been reported with olanzapine compared with placebo, haloperidol, or risperidone treatments. There is evidence that olanzapine may be effective in the treatment of mood disorders, psychosis associated with Alzheimer's disease, obsessive-compulsive disorder, pervasive developmental disorders, and delirium. Patients with schizophrenia have been successfully switched from other antipsychotics to olanzapine. In conclusion, olanzapine offers a significantly improved risk-to-benefit profile compared with haloperidol and possibly risperidone, and thus should be considered an important treatment option for schizophrenia and related disorders. SUMMARY Olanzapine is an innovative pharmaceutical product that has been prescribed to more than four million individuals worldwide. Olanzapine has a diverse neurotransmitter receptor binding profile that is similar to clozapine, with selective affinity for the serotonin receptors over the dopamine receptors. In vitro and in vivo preclinical experimentation has provided evidence for the antipsychotic efficacy of olanzapine with a low incidence of serious EPS. In addition, olanzapine has a pharmacokinetic profile that allows for single daily dosing and has minimal metabolic interactions with commonly coadminister
{"title":"Olanzapine: Preclinical and Clinical Profiles of a Novel Antipsychotic Agent","authors":"G. Tollefson, C. C. Taylor","doi":"10.1111/J.1527-3458.2000.TB00155.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00155.X","url":null,"abstract":"The novel antipsychotic agent olanzapine (Zyprexa, Eli Lilly and Company) is a thienobenzodiazepine analog marketed for the treatment of schizophrenia. Olanzapine's diverse receptor binding profile and greater affinity for serotonin receptors over dopamine receptors is thought to impart antipsychotic efficacy with a low incidence of serious extrapyramidal symptoms (EPS). With once daily dosing steady-state plasma concentrations reached within approximately 1 week. Olanzapine is extensively metabolized by the liver, is mostly excreted in the urine, and has few drug intractions. In clinical trials, the efficacy of olanzapine for treating schizophrenia is better than placebo and haloperidol and comparable to risperidone. Olanzapine may also ameliorate some comorbid symptoms including negative symptoms, depression, anxiety, substance abuse, and cognitive dysfunction, and it is effective in the long-term maintenance of response, treatment-resistance, and improving quality of life. The overall direct costs are lower with olanzapine treatment compared with haloperidol or risperidone treatment. In clinical trials, olanzapine demonstrates a favorable safety profile. The most frequently reported treatment-emergent adverse events are somnolence, schizophrenic reaction, insomnia, headache, agitation, rhinitis, and weight gain. Significantly fewer EPS (based on formal rating scales) and incidences of tardive dyskinesia have been reported for olanzapine compared with haloperidol. Olanzapine has not been associated with persistent elevations of prolactin above the upper limit of normal nor has it been associated with clinically significant changes in cardiac QTc interval. Fewer incidences of suicide attempts have been reported with olanzapine compared with placebo, haloperidol, or risperidone treatments. There is evidence that olanzapine may be effective in the treatment of mood disorders, psychosis associated with Alzheimer's disease, obsessive-compulsive disorder, pervasive developmental disorders, and delirium. Patients with schizophrenia have been successfully switched from other antipsychotics to olanzapine. In conclusion, olanzapine offers a significantly improved risk-to-benefit profile compared with haloperidol and possibly risperidone, and thus should be considered an important treatment option for schizophrenia and related disorders. \u0000 \u0000 \u0000 \u0000SUMMARY \u0000 \u0000Olanzapine is an innovative pharmaceutical product that has been prescribed to more than four million individuals worldwide. Olanzapine has a diverse neurotransmitter receptor binding profile that is similar to clozapine, with selective affinity for the serotonin receptors over the dopamine receptors. In vitro and in vivo preclinical experimentation has provided evidence for the antipsychotic efficacy of olanzapine with a low incidence of serious EPS. In addition, olanzapine has a pharmacokinetic profile that allows for single daily dosing and has minimal metabolic interactions with commonly coadminister","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"73 1","pages":"303-363"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82397187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00156.X
E. Giacobini
{"title":"Highlights from the Sixth International Stockholm/Springfield Meeting on Advances in Alzheimer Therapy Stockholm, Sweden, April 5–8, 2000","authors":"E. Giacobini","doi":"10.1111/J.1527-3458.2000.TB00156.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00156.X","url":null,"abstract":"","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"14 1","pages":"364-369"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82221693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2001.TB00210.X
S. Counts, S. Perez, Ulrika Kahl, Tamas Bartfai, Robert Bowser, Darlene C. Deecher, Deborah C. Mash, Jacqueline N. Crawley, E. Mufson
The neuropeptide galanin (GAL) is widely distributed in the mammalian CNS. Several lines of evidence suggest that GAL may play a critical role in cognitive processes such as memory and attention through an inhibitory modulation of cholinergic basal forebrain activity. Furthermore, GAL fibers hyperinnervate remaining cholinergic basal forebrain neurons in Alzheimer's disease (AD). This suggests that GAL activity impacts cholinergic dysfunction in advanced AD. Pharmacological and in vitro autoradiographic studies indicate the presence of heterogeneous populations of GAL receptor (GALR) sites in the basal forebrain which bind GAL with both high and low affinity. Interestingly, we have recently observed that GALR binding sites increase in the anterior basal forebrain in late-stage AD. Three G protein-coupled GALRs have been identified to date that signal through a diverse array of effector pathways in vitro, including adenylyl cyclase inhibition and phospholipase C activation. The repertoire and distribution of GALR expression in the basal forebrain remains unknown, as does the nature of GAL and GALR plasticity in the AD basal forebrain. Recently, GAL knockout and overexpressing transgenic mice have been generated to facilitate our understanding of GAL activity in basal forebrain function. GAL knockout mice result in fewer cholinergic basal forebrain neurons and memory deficits. On the other hand, mice overexpressing GAL display hyperinnervation of basal forebrain and memory deficits. These data highlight the need to explore further the putative mechanisms by which GAL signaling might be beneficial or deleterious for cholinergic cell survival and activity within basal forebrain. This information will be critical to understanding whether pharmacological manipulation of GALRs would be effective for the amelioration of cognitive deficits in AD.
{"title":"Galanin: neurobiologic mechanisms and therapeutic potential for Alzheimer's disease.","authors":"S. Counts, S. Perez, Ulrika Kahl, Tamas Bartfai, Robert Bowser, Darlene C. Deecher, Deborah C. Mash, Jacqueline N. Crawley, E. Mufson","doi":"10.1111/J.1527-3458.2001.TB00210.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2001.TB00210.X","url":null,"abstract":"The neuropeptide galanin (GAL) is widely distributed in the mammalian CNS. Several lines of evidence suggest that GAL may play a critical role in cognitive processes such as memory and attention through an inhibitory modulation of cholinergic basal forebrain activity. Furthermore, GAL fibers hyperinnervate remaining cholinergic basal forebrain neurons in Alzheimer's disease (AD). This suggests that GAL activity impacts cholinergic dysfunction in advanced AD. Pharmacological and in vitro autoradiographic studies indicate the presence of heterogeneous populations of GAL receptor (GALR) sites in the basal forebrain which bind GAL with both high and low affinity. Interestingly, we have recently observed that GALR binding sites increase in the anterior basal forebrain in late-stage AD. Three G protein-coupled GALRs have been identified to date that signal through a diverse array of effector pathways in vitro, including adenylyl cyclase inhibition and phospholipase C activation. The repertoire and distribution of GALR expression in the basal forebrain remains unknown, as does the nature of GAL and GALR plasticity in the AD basal forebrain. Recently, GAL knockout and overexpressing transgenic mice have been generated to facilitate our understanding of GAL activity in basal forebrain function. GAL knockout mice result in fewer cholinergic basal forebrain neurons and memory deficits. On the other hand, mice overexpressing GAL display hyperinnervation of basal forebrain and memory deficits. These data highlight the need to explore further the putative mechanisms by which GAL signaling might be beneficial or deleterious for cholinergic cell survival and activity within basal forebrain. This information will be critical to understanding whether pharmacological manipulation of GALRs would be effective for the amelioration of cognitive deficits in AD.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"57 1","pages":"445-70"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88165953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00153.X
G. John, Michel Perez, P. Pauwels, B. Grand, Y. Verscheure, F. Colpaert
We hypothesized that the limited acute therapeutic effectiveness of tryptamine derivatives in alleviating migraine headache could be explained by the relatively low intrinsic activity of these agents at 5-HT1B/1D receptors. Donitriptan is a novel arylpiperazide 5-hydroxytryptamine (5-HT) derivative which was designed to exploit the higher potency and efficacy properties of 5-HT compared to tryptamine at 5-HT1B/1D receptors. In vitro, donitriptan has subnanomolar affinity for nonhuman and human 5-HT1B/1D receptors and micromolar affinity for the 5-HTip subtype. Donitritpan potently inhibited forskolin-induced cAMP formation and enhanced specific GTP35γS specific binding to a greater extent than tryptamine derivatives and equivalent to 5-HT in C6 cells expressing human 5-HT1B or 5-HT1D receptors. Donitriptan produced more potent and larger amplitude increases in hyperpolarizing Ca2+-dependent K+ current than sumatriptan in guinea pig isolated trigeminal ganglion neurons, and was more potent than tryptamine derivatives in eliciting contractile responses in rabbit isolated saphenous vein rings. In vivo, donitriptan evoked more potent, longer-lasting and greater amplitude carotid vasoconstrictor responses than tryptamine derivatives in anesthetized pigs; and in contrast to sumatriptan, naratriptan or zolmitriptan, produced long-lasting, dose-dependent decreases in unilateral carotid blood flow in conscious dogs at doses from 0.63 mg/kg p.o. without affecting heart rate or behavior. Oral donitriptan also evoked hypothermic responses in guinea pigs suggesting that the compound gains access to the brain. Donitriptan is thus a selective, potent 5-HT1B/1D receptor agonist which can be distinguished from tryptamine derivatives in consistently exerting high intrinsic activity at these receptors in a series of vascular and neuronal models relevant to migraine. Advantages in terms of therapeutic effectiveness in the acute relief of migraine headache over currently available triptans can be expected to include greater response rates and consistency of pain relief, a lower incidence of migraine recurrence and better tolerability. The acute anti-migraine potential of the first high efficacy 5-HT1B/1D agonist of its kind, donitriptan, is currently being investigated in man.
{"title":"Donitriptan, a Unique High-Efficacy 5-HT1B/1D Agonist: Key Features and Acute Antimigraine Potential","authors":"G. John, Michel Perez, P. Pauwels, B. Grand, Y. Verscheure, F. Colpaert","doi":"10.1111/J.1527-3458.2000.TB00153.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00153.X","url":null,"abstract":"We hypothesized that the limited acute therapeutic effectiveness of tryptamine derivatives in alleviating migraine headache could be explained by the relatively low intrinsic activity of these agents at 5-HT1B/1D receptors. Donitriptan is a novel arylpiperazide 5-hydroxytryptamine (5-HT) derivative which was designed to exploit the higher potency and efficacy properties of 5-HT compared to tryptamine at 5-HT1B/1D receptors. \u0000 \u0000 \u0000 \u0000In vitro, donitriptan has subnanomolar affinity for nonhuman and human 5-HT1B/1D receptors and micromolar affinity for the 5-HTip subtype. Donitritpan potently inhibited forskolin-induced cAMP formation and enhanced specific GTP35γS specific binding to a greater extent than tryptamine derivatives and equivalent to 5-HT in C6 cells expressing human 5-HT1B or 5-HT1D receptors. Donitriptan produced more potent and larger amplitude increases in hyperpolarizing Ca2+-dependent K+ current than sumatriptan in guinea pig isolated trigeminal ganglion neurons, and was more potent than tryptamine derivatives in eliciting contractile responses in rabbit isolated saphenous vein rings. \u0000 \u0000 \u0000 \u0000In vivo, donitriptan evoked more potent, longer-lasting and greater amplitude carotid vasoconstrictor responses than tryptamine derivatives in anesthetized pigs; and in contrast to sumatriptan, naratriptan or zolmitriptan, produced long-lasting, dose-dependent decreases in unilateral carotid blood flow in conscious dogs at doses from 0.63 mg/kg p.o. without affecting heart rate or behavior. Oral donitriptan also evoked hypothermic responses in guinea pigs suggesting that the compound gains access to the brain. \u0000 \u0000 \u0000 \u0000Donitriptan is thus a selective, potent 5-HT1B/1D receptor agonist which can be distinguished from tryptamine derivatives in consistently exerting high intrinsic activity at these receptors in a series of vascular and neuronal models relevant to migraine. Advantages in terms of therapeutic effectiveness in the acute relief of migraine headache over currently available triptans can be expected to include greater response rates and consistency of pain relief, a lower incidence of migraine recurrence and better tolerability. The acute anti-migraine potential of the first high efficacy 5-HT1B/1D agonist of its kind, donitriptan, is currently being investigated in man.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"21 1","pages":"278-289"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81650589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-07DOI: 10.1111/J.1527-3458.2000.TB00143.X
R. Newcomb, Xiao-hua Chen, Robin Dean, G. Dayanithi, Cong Ruth, B. Szoke, J. Lemos, S. Bowersox, G. Miljanich
Calcium channels are represented by at least 9 distinct genes (calcium channel classes A-I), corresponding to at least 5 functional and pharmacological “types” (L, N, P/Q, R and T). Selective L-, N-, and T-type channel antagonists are either in clinical use or in late stage clinical trials, while antagonists of P/Q channels are known to be toxic. No selective ligand has been identified for the R-type (class E), and its function and pharmacology are consequently, poorly understood. We review recent work on the discovery and initial characterization of SNX-482, the first known selective antagonist of R-type calcium channels. SNX-482 is a 41 residue acidic peptide with three disulfide bonds that has been isolated from the venom of the African tarantula, Hysterocrates gigas. In cell-based assays, it is a potent and selective inhibitor of the class E or R-type calcium channel. SNX-482 blocks some but not all native R-type currents: it blocks an R-type current in vertebrate neurohypophysis, but it does not block an R-type current in cerebellar granule cells. The peptide blocks oxytocin but not vasopressin release, suggesting a possible utility for SNX-482 as a neuroendocrine modulator. The peptide possesses antiseizure activity in several animal models of epilepsy, suggesting that class E antagonists may have pharmacological use in seizure disorders.
{"title":"SNX‐482: A Novel Class E Calcium Channel Antagonist from Tarantula Venom","authors":"R. Newcomb, Xiao-hua Chen, Robin Dean, G. Dayanithi, Cong Ruth, B. Szoke, J. Lemos, S. Bowersox, G. Miljanich","doi":"10.1111/J.1527-3458.2000.TB00143.X","DOIUrl":"https://doi.org/10.1111/J.1527-3458.2000.TB00143.X","url":null,"abstract":"Calcium channels are represented by at least 9 distinct genes (calcium channel classes A-I), corresponding to at least 5 functional and pharmacological “types” (L, N, P/Q, R and T). Selective L-, N-, and T-type channel antagonists are either in clinical use or in late stage clinical trials, while antagonists of P/Q channels are known to be toxic. No selective ligand has been identified for the R-type (class E), and its function and pharmacology are consequently, poorly understood. We review recent work on the discovery and initial characterization of SNX-482, the first known selective antagonist of R-type calcium channels. SNX-482 is a 41 residue acidic peptide with three disulfide bonds that has been isolated from the venom of the African tarantula, Hysterocrates gigas. In cell-based assays, it is a potent and selective inhibitor of the class E or R-type calcium channel. SNX-482 blocks some but not all native R-type currents: it blocks an R-type current in vertebrate neurohypophysis, but it does not block an R-type current in cerebellar granule cells. The peptide blocks oxytocin but not vasopressin release, suggesting a possible utility for SNX-482 as a neuroendocrine modulator. The peptide possesses antiseizure activity in several animal models of epilepsy, suggesting that class E antagonists may have pharmacological use in seizure disorders.","PeriodicalId":10499,"journal":{"name":"CNS drug reviews","volume":"386 1","pages":"153-173"},"PeriodicalIF":0.0,"publicationDate":"2006-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77684760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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