Reuptake inhibitors



A reuptake inhibitor (RI), also known as a transporter blocker, is a drug which inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an increase in neurotransmission.

Many drugs utilize reuptake inhibition to exert their psychological and physiological effects, including various antidepressants, anxiolytics, stimulants, and anorectics, among others. Most known reuptake inhibitors affect the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. There are a number of pharmaceutical drugs and research chemicals that act as reuptake inhibitors for other neurotransmitters such as adenosine, GABA, glutamate, and the endocannabinoids as well, however.

Active site transporter substrates


Standard reuptake inhibitors are believed to act simply as competitive substrates that work by binding directly to the plasmalemma transporter of the neurotransmitter in question. They occupy the transporter in place of the respective neurotransmitter and competitively block it from being transported from the nerve terminal or synapse into the pre-synaptic neuron. With high enough doses, occupation becomes as much as 80-90%. At this level of inhibition, the transporter will be considerably less efficient at removing excess neurotransmitter from the synapse and this causes a substantial increase in the extracellular concentrations of the neurotransmitter and therefore an increase in overall neurotransmission.

Allosteric site transporter substrates


Alternatively, some reuptake inhibitors bind to allosteric sites and inhibit reuptake indirectly and noncompetitively.

Phencyclidine and related drugs such as benocyclidine, tenocyclidine, ketamine, and dizocilpine (MK-801), have been shown to inhibit the reuptake of the monoamine neurotransmitters. They appear to exert their reuptake inhibition by binding to vaguely characterized allosteric sites on each of the respective monoamine transporters. Benztropine, fluoxetine, mazindol, and vanoxerine also bind to these sites and have similar properties. In addition to their high affinity for the main site of the monoamine transporters, several competitive transporter substrates such as cocaine and indatraline have lower affinity for these allosteric sites as well.

A few of the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and the dextro-enantiomer of citalopram appear to be allosteric serotonin reuptake inhibitors. Instead of binding to the active site on the serotonin transporter, they bind to an allosteric site, which exerts its effects by causing conformational changes in the transporter protein, and thereby modulating the affinity of substrates for the active site. As a result, escitalopram has been marketed as an allosteric serotonin reuptake inhibitor. Notably, this allosteric site may be directly related to the above-mentioned PCP binding sites.

Two of the primary active constituents of the medicinal herb Hypericum perforatum (St. John's Wort) are hyperforin and adhyperforin. Hyperforin and adhyperforin are inhibitors of the reuptake of serotonin, norepinephrine, dopamine, GABA, and glutamate, and they exert these effects allosterically by binding to and activating the transient receptor potential cation channel TRPC6. Activation of TRPC6 induces the entry of calcium (Ca2+) and sodium (Na+) into the cell, which causes the effect.

Vesicular transporter substrates


A second type of reuptake inhibition affects vesicular transport, and blocks the intracellular repackaging of neurotransmitters into cytoplasmic vesicles. In contrast to plasmalemmal reuptake inhibitors, vesicular reuptake inhibitors do not increase the synaptic concentrations of a neurotransmitter, only the cytoplasmic concentrations; unless, that is, they also act as plasmalemmal transporter reversers via phosphorylation of the transporter protein, also known as a releasing agent. Pure vesicular reuptake inhibitors tend to actually lower synaptic neurotransmitter concentrations, as blocking the repackaging of, and storage of the neurotransmitter in question leaves them vulnerable to degradation via enzymes such as monoamine oxidase (MAO) which exist in the cytoplasm. With vesicular transport blocked, neurotransmitter stores quickly become depleted.

Reserpine (Serpasil) is an irreversible and competitive inhibitor of the vesicular monoamine transporter 2 (VMAT2), and is a classic example of a vesicular reuptake inhibitor.

Selective for one neurotransmitter

 * Adenosine reuptake inhibitor (AdoRI)
 * Dilazep (Cormelian), dipyridamole (Persantine), hexobendine (Ustimon), pentoxifylline (Trental)
 * Dopamine reuptake inhibitor (DRI)
 * Amfonelic acid (AFA; WIN 25,978), benocyclidine (BTCP; GK-13), troparil (β-CPT; WIN 35,065-2), vanoxerine (GBR-12,909)
 * Endocannabinoid reuptake inhibitor (eCBRI)
 * AM-404, O-2093, OMDM-2, UCM-707, VDM-11
 * Glutamate reuptake inhibitor (GluRI) or excitatory amino acid reuptake inhibitor (EAARI)
 * Dihydrokainic acid, PDC, WAY-213,613
 * GABA reuptake inhibitor (GRI)
 * Deramciclane (EGIS-3886), nipecotic acid, tiagabine (Gabitril)
 * Glycine reuptake inhibitor (GlyRI)
 * ACPPB, ALX-5407, glycyldodecylamide, ORG-24,589, sarcosine, SSR-103,800, SSR-504,734
 * Norepinephrine reuptake inhibitor (NRI) or Adrenergic reuptake inhibitor (ARI))
 * Atomoxetine (Strattera), nisoxetine (LY-94,939), reboxetine (Edronax, Vestra), viloxazine (Vivalan)
 * Serotonin reuptake inhibitor (SRI)
 * Escitalopram (Lexapro, Cipralex), fluoxetine (Prozac), sertraline (Zoloft, Lustral)

Selective for several neurotransmitters

 * Serotonin-norepinephrine reuptake inhibitor (SNRI)
 * Desvenlafaxine (Pristiq), duloxetine (Cymbalta), milnacipran (Dalcipran, Ixel, Savella), venlafaxine (Effexor)
 * Norepinephrine-dopamine reuptake inhibitor (NDRI)
 * Amineptine (Survector), bupropion (Wellbutrin, Zyban), methylenedioxypyrovalerone, methylphenidate (Ritalin, Concerta), pipradrol (Meretran)
 * Serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI)
 * Cocaine, indatraline (Lu-19-005), nefopam (Acupan), tesofensine (NS-2330)
 * Serotonin-norepinephrine-dopamine-GABA-glutamate reuptake inhibitor
 * Adhyperforin, hyperforin