Biomedical Engineering Reference
In-Depth Information
gene family also includes intracellular vesicular transporters, such as the vesicular glutamate trans-
porters (SLC17), the vesicular monoamine transporters (SLC18), and the vesicular inhibitory amino
acid transporters (SLC32).
Notwithstanding the huge number of transport proteins present in the human body, relatively
few of them are targets for the action of drugs. It might even be argued that transport proteins are
relatively overlooked as drug targets in spite of their critical physiological functions and some real
“success stories,” such as, inhibitors of the gastric ATP-driven proton pump, used against peptic
ulcers, and inhibitors of monoamine transporters, used against depression/anxiety disorders (see
Chapter 18). In this chapter, we focus on the monoamine transporters and then on the neurotransmit-
ter transporters belonging to the SLC6 family (also named neurotransmitter:sodium symporters or
Na-/Cl-dependent transporters) (Table 14.1). Indeed, the SLC6 transporters represent important targets
for several drugs including not only medicines used against depression/anxiety but also against
TABLE 14.1
SLC6 Gene Family Neurotransmitter Transporters
Endogenous
Substrates
Synthetic
Substrates
Therapeutic
Use/Potential
Potent Inhibitors
Dopamine transporter
(DAT)
Dopamine
Norepinephrine
Epinephrine
Amphetamine
MPP+
CFT, GBR12,909
benztropine, mazindol,
RTI-55, Cocaine, Zn
2+
ADHD (amphetamines),
Parkinsonism?
(inhibitors)
Serotonin transporter
(SERT or 5-HTT)
5-HT
p
-Cl-
Amphetamine
MDMA
(“ecstasy”)
Citalopram, escitalopram,
l uoxetin, paroxetin,
sertraline, imipramine,
cocaine, RTI-55
Depression, anxiety,
OCD (inhibitors)
Norepinephrine
transporter (NET
or NAT)
Dopamine
Norepinephrine
Epinephrine
Amphetamine
MPP+
Nisoxetine, nortriptyline,
desipramine, duloxetine,
venlafaxine, mazindol
Depression (inhibitors)
Glycine transporter 1
(GlyT1)
Glycine
—
(R)NFPS (ALX5407),
NPTS, Org24598
Schizophrenia?
Psychosis?
Dementia? (inhibitors)
Glycine transporter 2
(GlyT2)
Glycine
—
ALX1393, ALX1405
Org25543
Anticonvulsant?
Analgesic? (inhibitors)
GABA transporter 1
(GAT-1)
GABA
—
Tiagabine,
SKF89976A, THPO,
exo-THPO
Epilepsy (tiagabine)
GABA transporter 2
(GAT-2 equivalent
to mouse GAT-3)
GABA
beta-Ala
—
—
?
GABA transporter 3
(GAT-3 equivalent
to mouse GAT-4)
GABA
beta-Ala
—
SNAP5114
?
GABA transporter 4
(GAT-4, equivalent to
BGT1 or mouse GAT-2)
GABA
Betaine
—
EF-1502, NNC052090,
THPO Zn
2+
Epilepsy? (inhibitors)
EF-1502
Note:
The known neurotransmitter transporters belonging to the SLC6 gene family with their respective substrates, inhibitors,
and potential therapeutic use.
Abbreviations:
CFT, 2β-carbomethoxy-3β-(4-l uorophenyl)tropane; MDMA, 3, 4-methylenedioxymethamphetamine; MPP+,
1-methy l-4-phenylpyridinium; (R)NFPS,
N
-[3-(40-l uorophenyl)-3-(40-phenylphenoxy) propyl]sarcosine;
NPTS,
N
-[3-phenyl-3-(40-(4-toluoyl) phenoxy)propyl]sarcosine; THPO, (4,5,6,7-tetrahydroisoxazolo[4,5-
c
]
pyridine-3-ol); ADHD, attention dei cit hyperactivity disorder; OCD, obsessive-compulsive disorder.
Exo-THPO: 4-amino-4,5,6,7-tetrahydrobenzo[
d
]isoxazol-3-ol.
