Switching Activity of Allosteric Modulators Controlled by a Cluster of Residues Forming a Pressure Point in the mGluR5 GPCR

2017 ◽  
pp. 147-174
Author(s):  
Michael Sabio ◽  
Sid Topiol
Keyword(s):  
Allosteric Modulators ◽  
Switching Activity ◽  
Pressure Point

NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites

2019 ◽  
Vol 19 (24) ◽  
pp. 2239-2253 ◽  
Author(s):  
Paul J. Goldsmith
Keyword(s):  
Binding Sites ◽  
Receptor Activation ◽  
Research Area ◽  
Allosteric Modulators ◽  
Nonselective Cation Channels ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Excitatory Neurotransmission ◽  
Psychiatric Conditions ◽  
High Level

The N-methyl-D-aspartate receptor (NMDAR) is a member of the ionotropic glutamate receptor (iGluR) family that plays a crucial role in brain signalling and development. NMDARs are nonselective cation channels that are involved with the propagation of excitatory neurotransmission signals with important effects on synaptic plasticity. NMDARs are functionally and structurally complex receptors, they exist as a family of subtypes each with its own unique pharmacological properties. Their implication in a variety of neurological and psychiatric conditions means they have been a focus of research for many decades. Disruption of NMDAR-related signalling is known to adversely affect higherorder cognitive functions (e.g. learning and memory) and the search for molecules that can recover (or even enhance) receptor output is a current strategy for CNS drug discovery. A number of positive allosteric modulators (PAMs) that specifically attempt to overcome NMDAR hypofunction have been discovered. They include various chemotypes that have been found to bind to several different binding sites within the receptor. The heterogeneity of chemotype, binding site and NMDAR subtype provide a broad landscape of ongoing opportunities to uncover new features of NMDAR pharmacology. Research on NMDARs continues to provide novel mechanistic insights into receptor activation and this review will provide a high-level overview of the research area and discuss the various chemical classes of PAMs discovered so far.

Tuning Down the Pain – An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses

2020 ◽  
Vol 20 (31) ◽  
pp. 2852-2865 ◽  
Author(s):  
Damian Bartuzi ◽  
Tomasz M. Wróbel ◽  
Agnieszka A. Kaczor ◽  
Dariusz Matosiuk
Keyword(s):  
Side Effects ◽  
Opioid Receptors ◽  
Pain Perception ◽  
Allosteric Modulation ◽  
Allosteric Modulators ◽  
Signaling Mechanisms ◽  
Main Target ◽  
Allosteric Sites ◽  
Biased Signaling ◽  
Opioid Signaling

Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms. In this review, we focus on recently discovered allosteric modulators of opioid receptors, insights into phenomena underlying their action, as well as on how they extend our understanding of mechanisms of previously known compounds. A brief overlook of their synthesis is also presented.

QSAR Study of Anticonvulsant Negative Allosteric Modulators of the AMPA Receptor

2004 ◽  
Vol 47 (7) ◽  
pp. 1860-1863 ◽  
Author(s):  
Antonio Macchiarulo ◽  
Laura De Luca ◽  
Gabriele Costantino ◽  
Maria Letizia Barreca ◽  
Rosaria Gitto ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Allosteric Modulators ◽  
Qsar Study
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