A PHP Error was encountered

Severity: Warning

Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests

Filename: helpers/my_audit_helper.php

Line Number: 143

Backtrace:

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 994
Function: getPubMedXML

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3134
Function: GetPubMedArticleOutput_2016

File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global

File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword

File: /var/www/html/index.php
Line: 316
Function: require_once

MEPIRAPIM-derived synthetic cannabinoids inhibit T-type calcium channels with divergent effects on seizures in rodent models of epilepsy. | LitMetric

AI Article Synopsis

  • T-type Ca channels (Ca3) are potential targets for treating neurological disorders like epilepsy and pain, with a focus on developing new inhibitors.
  • MEPIRAPIM and its derivatives, SB2193 and SB2193F, have been identified as brain-penetrant Ca3 inhibitors that show effective inhibition in laboratory assays, making them promising candidates for further research.
  • Although SB2193 demonstrated protection against specific seizure types in mouse models, it was ineffective against spontaneous seizures in Dravet syndrome and absence seizures in GAERS, indicating a need for more targeted therapeutic strategies.

Article Abstract

T-type Ca channels (Ca3) represent emerging therapeutic targets for a range of neurological disorders, including epilepsy and pain. To aid the development and optimisation of new therapeutics, there is a need to identify novel chemical entities which act at these ion channels. A number of synthetic cannabinoid receptor agonists (SCRAs) have been found to exhibit activity at T-type channels, suggesting that cannabinoids may provide convenient chemical scaffolds on which to design novel Ca3 inhibitors. However, activity at cannabinoid type 1 (CB) receptors can be problematic because of central and peripheral toxicities associated with potent SCRAs. The putative SCRA MEPIRAPIM and its analogues were recently identified as Ca3 inhibitors with only minimal activity at CB receptors, opening the possibility that this scaffold may be exploited to develop novel, selective Ca3 inhibitors. Here we present the pharmacological characterisation of SB2193 and SB2193F, two novel Ca3 inhibitors derived from MEPIRAPIM. The potency of SB2193 and SB2193F was evaluated using a fluorometric Ca flux assay and confirmed using whole-cell patch-clamp electrophysiology. docking to the cryo-EM structure of Ca3.1 was also performed to elucidate structural insights into T-type channel inhibition. Next, pharmacokinetic parameters in mouse brain and plasma were determined using liquid chromatography-mass spectroscopy. Finally, anticonvulsant activity was assayed in established genetic and electrically-induced rodent seizure models. Both MEPIRAPIM derivatives produced potent inhibition of Ca3 channels and were brain penetrant, with SB2193 exhibiting a brain/plasma ratio of 2.7. SB2193 was further examined in mouse seizure models where it acutely protected against 6 Hz-induced seizures. However, SB2193 did not reduce spontaneous seizures in the mouse model of Dravet syndrome, nor absence seizures in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Surprisingly, SB2193 appeared to increase the incidence and duration of spike-and-wave discharges in GAERS animals over a 4 h recording period. These results show that MEPIRAPIM analogues provide novel chemical scaffolds to advance Ca3 inhibitors against certain seizure types.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110893PMC
http://dx.doi.org/10.3389/fphys.2023.1086243DOI Listing

Publication Analysis

Top Keywords

ca3 inhibitors
20
t-type channels
8
novel chemical
8
chemical scaffolds
8
novel ca3
8
mepirapim analogues
8
sb2193 sb2193f
8
seizure models
8
ca3
7
sb2193
6

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!

A PHP Error was encountered

Severity: Notice

Message: fwrite(): Write of 34 bytes failed with errno=28 No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 272

Backtrace:

A PHP Error was encountered

Severity: Warning

Message: session_write_close(): Failed to write session data using user defined save handler. (session.save_path: /var/lib/php/sessions)

Filename: Unknown

Line Number: 0

Backtrace: