User:Ikenhower/sandbox

(1) mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning

https://www.nature.com/articles/npp200930

-Potential use: using a PAM 4-Nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide to induce LTP and LTD in mGluR5 in the hippocampus, helps treat the negative symptoms (cognitive deficits) of schizophrenia, including learning and memory

-5MPEP is a neutral modulator that blocks the other one's activity but doesn't really have any activity itself (must occupy the same site)

(2) Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: Advantages and limitations

https://www.sciencedirect.com/science/article/pii/S0006295211002917

-nAChR receptors may be desensitized too quickly if agonists are used to activate them.

(3) Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors

https://www.jneurosci.org/content/25/39/9027.full

-One way an allosteric modulator, or "potentiator" can modulate receptor activity is to slow deactivation of the receptor. This is accomplished in the AMPA receptor using aniracetam or CX614 to bind the outside of the receptor's clam shell, stabilizing the closed conformation.

-If AMPA receptors can stay open longer, short-term memory improves.

-PAMs can slow desensitization, aniracetam does this too

(4) Design and Synthesis of Novel Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors with the Ability To Rescue Auditory Gating Deficit in Mice

https://www.ncbi.nlm.nih.gov/pubmed/29587480

'''-Major advantage: PAMs don't activate the receptor in places or at times that aren't normal. The agonist is still required in order to activate the channel.'''

'''-There's a Type I PAM (maintains receptor kinetics) and a Type II PAM (alters receptor kinetics). Both affect current. (Since they're positive, they increase current)'''

(5) https://www.sciencedirect.com/topics/medicine-and-dentistry/allosteric-modulator

-Modulation of the GABA receptor may help sufferers of anxiety and sleep disorders.

-Barbiturates work via allosteric modulation .

-Prevention of desensitization comes from stabilizing the Ligand Binding Domain dimer interface.

-The hinge region of an AMPA receptor is one target for PAMs

-The Amino-Terminal Domain is another target on NMDA receptors for allosteric modulators, generally to the effect of keeping the channel closed.

-It is believed that the modulators change the 3 dimensional conformation of the binding site itself

-CaSR receptors are modulated by aromatic amino acids, threonine and alanine.

-Large peptides can be allosteric modulators, such as beta-amyloid peptides (overproduced in Alzheimer patients) positively modulating CaSR

'''-The mechanism behind glutathione enhancing taste could be linked to the CaSR receptors found in taste buds. Glutathione is another PAM for CaSR'''

-pH and ionic strength also modulate receptor sensitivity

SectionsMechanisms

-One way an allosteric modulator, or "potentiator" can modulate receptor activity is to slow deactivation of the receptor. This is accomplished in the AMPA receptor using aniracetam or CX614 to bind the outside of the receptor's clam shell, stabilizing the closed conformation.

-PAMs can slow desensitization, aniracetam does this too

Known Capabilities

-Potential use: using a PAM 4-Nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide to induce LTP and LTD in mGluR5 in the hippocampus, helps treat the negative symptoms (cognitive deficits) of schizophrenia, including learning and memory

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