scholarly journals A Comparison of the 2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Sarah Nickolls ◽  
Hannah Mace ◽  
Rebecca Fish ◽  
Michelle Edye ◽  
Rachel Gurrell ◽  
...  

receptors containingα2/3 subunits are current targets in the battle to develop new pain medications, as they are expressed in the spinal cord where increasing inhibitory drive should result in analgesia. However, this approach is prone to a range of side effects including sedation, cognitive impairment, and abuse as a consequence of the widespread influence of GABA. The ability to make subtype selective low-efficacy benzodiazepine compounds, which potentiate the action of GABA at specificαsubunits, has the potential to reduce this side effect profile. In this study, we have investigated the effects of the medium-efficacy positive allosteric modulator (PAM) L-838,417 and the low-efficacy PAM TPA023 in a number of preclinical inflammatory and neuropathic pain models. We conclude that either the higher level of efficacy atα2/3 or efficacy atα5 is required for compounds to have a significant analgesic effect in a range of models, and, therefore, although the side-effect profile of compounds can be reduced compared to typical benzodiazepines, it is unlikely that it can be completely eliminated.

2013 ◽  
Vol 65 ◽  
pp. 156-164 ◽  
Author(s):  
Kelen Freitas ◽  
Sudeshna Ghosh ◽  
F. Ivy Carroll ◽  
Aron H. Lichtman ◽  
M. Imad Damaj

2017 ◽  
Vol 8 (6) ◽  
pp. 1305-1312 ◽  
Author(s):  
Lakeisha A. Lewter ◽  
Janet L. Fisher ◽  
Justin N. Siemian ◽  
Kashi Reddy Methuku ◽  
Michael M. Poe ◽  
...  

2019 ◽  
Vol 22 (10) ◽  
pp. 640-650 ◽  
Author(s):  
Shaun Hopper ◽  
Geoffrey Mark Pavey ◽  
Andrea Gogos ◽  
Brian Dean

Abstract Background Preclinical and some human data suggest allosteric modulation of the muscarinic M1 receptor (CHRM1) is a promising approach for the treatment of schizophrenia. However, it is suggested there is a subgroup of participants with schizophrenia who have profound loss of cortical CHRM1 (MRDS). This raises the possibility that some participants with schizophrenia may not respond optimally to CHRM1 allosteric modulation. Here we describe a novel methodology to measure positive allosteric modulation of CHRM1 in human CNS and the measurement of that response in the cortex, hippocampus, and striatum from participants with MRDS, non-MRDS and controls. Methods The cortex (Brodmann’s area 6), hippocampus, and striatum from 40 participants with schizophrenia (20 MRDS and 20 non-MRDS) and 20 controls were used to measure benzyl quinolone carboxylic acid-mediated shift in acetylcholine displacement of [3H]N-methylscopolamine using a novel in situ radioligand binding with autoradiography methodology. Results Compared with controls, participants with schizophrenia had lower levels of specific [3H]N-methylscopolamine binding in all CNS regions, whilst benzyl quinolone carboxylic acid-modulated binding was less in the striatum, Brodmann’s area 6, dentate gyrus, and subiculum. When divided by subgroup, only in MRDS was there lower specific [3H]N-methylscopolamine binding and less benzyl quinolone carboxylic acid-modulated binding in all cortical and subcortical regions studied. Conclusions In a subgroup of participants with schizophrenia, there is a widespread decreased responsiveness to a positive allosteric modulator at the CHRM1. This finding may have ramifications it positive allosteric modulators of the CHRM1 are used in clinical trials to treat schizophrenia as some participants may not have an optimal response.


2016 ◽  
Vol 173 (16) ◽  
pp. 2506-2520 ◽  
Author(s):  
Deniz Bagdas ◽  
Jenny L Wilkerson ◽  
Abhijit Kulkarni ◽  
Wisam Toma ◽  
Shakir AlSharari ◽  
...  

2015 ◽  
Vol 40 (13) ◽  
pp. 2948-2959 ◽  
Author(s):  
Bogna M Ignatowska-Jankowska ◽  
Gemma L Baillie ◽  
Steven Kinsey ◽  
Molly Crowe ◽  
Sudeshna Ghosh ◽  
...  

2019 ◽  
Vol 30 (5) ◽  
pp. 452-461 ◽  
Author(s):  
Megan J. Moerke ◽  
Guanguan Li ◽  
Lalit K. Golani ◽  
James Cook ◽  
S. Stevens Negus

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