p‐Methylthioamphetamine and 1‐(m‐chlorophenyl)piperazine, two non‐neurotoxic 5‐HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5‐HT nerve endings in vitro

Gobbi, Marco; Moia, M.; Pirona, Lorenza; Ceglia, Ilaria; Reyes‐Parada, Miguel; Scorza, Cecilia; Mennini, Tiziana

doi:10.1046/j.1471-4159.2002.01073.x

Cited by 44 publications

(66 citation statements)

References 33 publications

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“…Glutamate release measurements were performed on superfused hippocampal synaptosomes from vehicle-and BoNT/Etreated rats (n ϭ 7 per group), 1 d after intrahippocampal injection of 40 ng of kainic acid (see below for details). Preparation of synaptosomes was as described by Gobbi et al (2002), and release of glutamate was assessed according to Di Stasi et al (2002). Synaptosomes were depolarized by a 90 s pulse of 35 mM KCl.…”

Section: Methodsmentioning

confidence: 99%

Antiepileptic Effects of Botulinum Neurotoxin E

Costantin¹,

Bozzi²,

Richichi³

et al. 2005

J. Neurosci.

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Experimental studies suggest that the delivery of antiepileptic agents into the seizure focus might be of potential utility for the treatment of focal-onset epilepsies. Botulinum neurotoxin E (BoNT/E) causes a prolonged inhibition of neurotransmitter release after its specific cleavage of the synaptic protein synaptosomal-associated protein of 25 kDa (SNAP-25). Here, we show that BoNT/E injected into the rat hippocampus inhibits glutamate release and blocks spike activity of pyramidal neurons. BoNT/E effects persist for at least 3 weeks, as determined by immunodetection of cleaved SNAP-25 and loss of intact SNAP-25. The delivery of BoNT/E to the rat hippocampus dramatically reduces both focal and generalized kainic acid-induced seizures as documented by behavioral and electrographic analysis. BoNT/E treatment also prevents neuronal loss and long-term cognitive deficits associated with kainic acid seizures. Moreover, BoNT/Einjected rats require 50% more electrical stimulations to reach stage 5 of kindling, thus indicating a delayed epileptogenesis. We conclude that BoNT/E delivery to the hippocampus is both antiictal and antiepileptogenic in experimental models of epilepsy.

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Section: Methodsmentioning

confidence: 99%

Antiepileptic Effects of Botulinum Neurotoxin E

Costantin¹,

Bozzi²,

Richichi³

et al. 2005

J. Neurosci.

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“…Usually, these results are interpreted as an indication of compensatory upregulation in postsynaptic serotonin receptor function during depression and subsequent receptor normalization after BLT. However, besides being an agonist at serotonin receptors, mCPPFsimilar to TYRFelicits a nonexocytotic, 5-HTTmediated exchange diffusion process (Gobbi et al, 2002;Rothman and Baumann, 2002). Hence, the enhanced mCPP response in SAD and its normalization after BLT could in part also be secondary to enhanced CNS 5-HTT function normalizing after successful BLT.…”

Section: -Htt Function In Sadmentioning

confidence: 99%

Enhanced Serotonin Transporter Function during Depression in Seasonal Affective Disorder

Willeit

Sitte

Thierry

et al. 2007

Neuropsychopharmacol

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Decreased synaptic serotonin during depressive episodes is a central element of the monoamine hypothesis of depression. The serotonin transporter (5-HTT, SERT) is a key molecule for the control of synaptic serotonin levels. Here we aimed to detect state-related alterations in the efficiency of 5-HTT-mediated inward and outward transport in platelets of drug-free depressed patients suffering from seasonal affective disorder (SAD). 5-HTT turnover rate, a measure for the number of inward transport events per minute, and tyramineinduced, 5-HTT-mediated outward transport were assessed at baseline, after 4 weeks of bright light therapy, and in summer using a case-control design in a consecutive sample of 73 drug-free depressed patients with SAD and 70 nonseasonal healthy controls. Patients were drug-naive or medication-free for at least 6 months prior to study inclusion, females patients were studied in the follicular phase of the menstrual cycle. All participants were genotyped for a 5-HTT-promoter polymorphism (5-HTTLPR) to assess the influence of this polymorphism on 5-HTT parameters. Efficiency of 5-HTT-mediated inward (p ¼ 0.014) and outward (p ¼ 0.003) transport was enhanced in depressed patients. Both measures normalized toward control levels after therapy and in natural summer remission. Changes in outward transport showed a clear correlation with treatment response (r ¼ 0.421, p ¼ 0.001). Changes in inward transport were mediated by changes in 5-HTT transport efficiency rather than affinity or density. 5-HTTLPR was not associated with any of the 5-HTT parameters. In sum, we conclude that the 5-HTT is in a hyperfunctional state during depression in SAD and normalizes after light therapy and in natural summer remission.

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“…It was identified to be an atypical opioid, both structurally and pharmacologically. It acts as a weak μ opioid receptor agonist and serotonin reuptake and norepinephrine reuptake inhibitor [11,12] . Its O-desmethyl metabolite (M1) is much more potent on the μ opioid receptor [13] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel μ opioid receptor ligands

Shen

Qian

et al. 2015

Acta Pharmacol Sin

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Aim: Tramadol is an atypical opioid analgesic with low potential for tolerance and addiction. However, its opioid activity is much lower than classic opiates such as morphine. To develop novel analgesic and further explore the structure activity relationship (SAR) of tramadol skeleton. Methods: Based on a three-dimensional (3D) structure superimposition and molecular docking study, we found that M1 (the active metabolite of tramadol) and morphine have common pharmacophore features and similar binding modes at the μ opioid receptor in which the substituents on the nitrogen atom of both compounds faced a common hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. In this study, N-phenethylnormorphine was docked to the μ opioid receptor. It was found that the N-substituted group of N-phenethylnormorphine extended into a hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. This hydrophobic interaction may contribute to the improvement of its opioid activities as compared with morphine. The binding modes of M1, morphine and N-phenethylnormorphine overlapped, indicating that the substituent on the nitrogen atoms of the three compounds may adopt common orientations. A series of N-phenylalkyl derivatives from the tramadol scaffold were designed, synthesized and assayed in order to generate a new type of analgesics. Results: As a result, compound 5b was identified to be an active candidate from these compounds. Furthermore, the binding modes of 5b and morphine derivatives in the μ opioid receptor were comparatively studied. Conclusion: Unlike morphine-derived structures in which bulky N-substitution is associated with improved opioid-like activities, there seems to be a different story for tramadol, suggesting the potential difference of SAR between these compounds. A new type of interaction mechanism in tramadol analogue (5b) was discovered, which will help advance potent tramadol-based analgesic design.

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p‐Methylthioamphetamine and 1‐(m‐chlorophenyl)piperazine, two non‐neurotoxic 5‐HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5‐HT nerve endings in vitro

Cited by 44 publications

References 33 publications

Antiepileptic Effects of Botulinum Neurotoxin E

Antiepileptic Effects of Botulinum Neurotoxin E

Enhanced Serotonin Transporter Function during Depression in Seasonal Affective Disorder

Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel μ opioid receptor ligands

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