Drug Modulation of Endogenous Signaling

5 steps of endogenous chemical signaling

-synthesis

-release

-distribution

-binding

-removal

ACh synthesis

acetyl CoA + choline --> acetylcholine + CoA by choline acetyltransferase (ChAT)

ChAT (choline acetyltransferase)

enzyme that synthesizes acetylcholine from acetyl CoA and choline

ACh removal

ACh → choline + acetate by acetylcholinesterase (AChE)

α-NETA

drug that inhibits choline acetyltransferase (ChAT), resulting in reduced ACh synthesis

Botox (botulinum toxin)

toxin that cleaves SNARE proteins to block vesicular release of ACh, resulting in decreased synaptic ACh

neostigmine

drug that inhibits acetylcholinesterase (AChE), preventing ACh degradation resulting in increased ACh signaling

dopamine synthesis

-tyrosine → L-DOPA by tyrosine hydroxylase (TH)

-L-DOPA → DA by DOPA decarboxylase (DDC)

tyrosine hydroxylase (TH)

enzyme that converts tyrosine to L-DOPA

DDC (DOPA decarboxylase)

enzyme that converts L-DOPA into dopamine

dopamine transporter (DAT)

membrane protein on presynaptic cell that reuptakes dopamine from the synapse

AMPT

a drug that inhibits tyrosine hydroxylase (TH), resulting in decreased synthesis of catecholamines such as dopamine

amphetamine

drug that causes vesicular release of DA into cytoplasm, resulting in DA exiting the cell through DAT

cocaine

drug that blocks DAT to prevent DA reuptake from the synapse, resulting in increases DA signaling

CGRP synthesis

encoded in the genome, thus it is expressed and translated into the peptide

peptidases

enzymes that break down proteins, such as CGRP, into peptide fragments

fremanezumab

drug that binds to extracellular CGRP to reduce free peptide available

orthosteric binding site

binding site on a receptor to which the endogenous ligand binds

allosteric binding site

binding site on a receptor that is a different site from where the endogenous ligand binds

orthosteric binding

binding competes with endogenous ligand for the receptor

signaling bias

a measure of the degree to which a drug can selectively activate one signaling pathway over another signaling pathway

example of signaling bias

in MOR signaling, a lower threshold of receptor activation is necessary for recruitment of G-protein signaling versus β-arrestin signaling

allosteric binding

binding to separate site from where orthosteric ligand binds, but affects the receptor's response to orthosteric ligand (affinity or efficacy) either positively or negatively

pure allosteric modulators

allosteric modulators that have no effect on receptor activity on their own

positive allosteric modulator (PAM)

allosteric modulator that increases the net signal by orthosteric ligand by increasing its affinity or efficacy for the receptor

GABAa receptor

ionotropic, pentameric receptor for GABA that allows Cl- ions to enter the cell, thereby inhibiting cell firing; has multiple allosteric sites for benzodiazepines, barbiturates, ethanol, and neurosteroids

GABA binding site

α-β interfaces of GABAa receptor

benzodiazepine binding site

α-γ interfaces of GABAa receptors

benzodiazepines, barbiturates

______ increase frequency of GABAa receptor channel opening in the presence of GABA, while ______ prolong duration of GABAa receptor channel opening in the presence of GABA

negative allosteric modulator (NAM)

allosteric modulator that decreases the net signal by orthosteric ligand by decreasing its affinity or efficacy for the receptor

DMCM

negative allosteric modulator that is a BZ binding site inverse agonist, decreases GABA's action and inhibits BZ action

silent allosteric modulator (SAM)

allosteric modulators that bind to allosteric site on receptor but have no effect on orthosteric ligand's affinity or efficacy; act as allosteric site antagonist

flumazenil

silent allosteric modulator that is an antagonist of the BZ site but has no effect on GABA's action

allosteric agonists

allosteric modulators that have some level of agonist activity on their own

allosteric agonist signaling bias

a biased ability to increase or decrease orthosteric ligand action for different signaling pathways

ago-PAMs and ago-NAMs

positive and negative allosteric modulators that have some level of agonist activity on their own

spatial resolution (allosteric modulators)

allosteric modulators act only where the endogenous ligand is released

temporal resolution (allosteric modulators)

allosteric modulators act only when the endogenous ligand is released