In
pharmacology, an
indirect agonist or
indirect-acting agonist is a substance that enhances the release or action of an
endogenous neurotransmitter but has no specific
agonist activity at the neurotransmitter receptor itself. Indirect agonists work through varying mechanisms to achieve their effects, including transporter blockade, induction of transmitter release, and inhibition of transmitter breakdown.
Mechanisms of indirect agonism
Reuptake inhibition
Cocaine is a monoamine transporter blocker and, thus, an indirect agonist of dopamine receptors.
binds the dopamine transporter (DAT), blocking the protein's ability to uptake
dopamine from the
synaptic cleft and also blocking DAT from terminating
dopamine signaling. Blockage of DAT increases the
extracellular concentration of
dopamine, therefore increasing the amount of
dopamine receptor binding and signaling.
Dipyridamole inhibits reuptake of adenosine, resulting in greater extracellular concentrations of adenosine. Dipyridamole also inhibits the enzyme adenosine deaminase, the enzyme that catalyzes the breakdown of adenosine.
Evoking transmitter release
Fenfluramine is an indirect agonist of serotonin receptors.
binds to the serotonin transporter, blocking
serotonin reuptake. However,
fenfluramine also acts to induce non-
exocytosis serotonin release; in a mechanism similar to that of
methamphetamine in
dopamine neurons,
fenfluramine binds to VMAT2, disrupting the compartmentalization of
serotonin into
Synaptic vesicle and increasing the concentration of
serotonin available for drug-induced release.
