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Indirect agonist

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.[1] Cocaine 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.[2] Fenfluramine binds to the serotonin transporter, blocking serotonin reuptake. However, fenfluramine also acts to induce non-exocytotic serotonin release; in a mechanism similar to that of methamphetamine in dopamine neurons, fenfluramine binds to VMAT2, disrupting the compartmentalization of serotonin into vesicles and increasing the concentration of cytoplasmic serotonin available for drug-induced release.[3]


  1. ^ Katz JL, Izenwasser S, Terry P (2000). "Relationships among dopamine transporter affinities and cocaine-like discriminative-stimulus effects". Psychopharmacology. 148 (1): 90–8. doi:10.1007/s002130050029. PMID 10663422.
  2. ^ Wang YX, Bowersox SS, Pettus M, Gao D (1999). "Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy". J. Pharmacol. Exp. Ther. 291 (3): 1008–16. PMID 10565818.
  3. ^ Baumann MH, Ayestas MA, Dersch CM, Partilla JS, Rothman RB (2000). "Serotonin transporters, serotonin release, and the mechanism of fenfluramine neurotoxicity". Ann. N. Y. Acad. Sci. 914 (1): 172–86. doi:10.1111/j.1749-6632.2000.tb05194.x. PMID 11085319.