Biomedical Engineering Reference
In-Depth Information
18
Dopamine and Serotonin
Benny Bang-Andersen and Klaus P. Bøgesø
CONTENTS
18.1 Introduction......................................................................................................................... 299
18.2 ReceptorLigands................................................................................................................300
18.2.1 AntipsychoticDrugs..............................................................................................300
18.2.1.1 Classical Antipsychotic Drugs ...............................................................300
18.2.1.2 Atypical Antipsychotic Drugs................................................................ 302
18.3 TransporterLigands............................................................................................................304
18.3.1 AntidepressantDrugs.............................................................................................304
18.3.1.1 First Generation Drugs........................................................................... 305
18.3.1.2 The Selective Serotonin Reuptake Inhibitors......................................... 306
18.3.1.3 Discovery of Escitalopram—An Allosteric Serotonin
Reuptake Inhibitor.................................................................................. 309
18.3.1.4 The SSRI Pharmacophore and SERT Homology Model ....................... 310
18.4 Concluding Remarks........................................................................................................... 312
Further Readings ............................................................................................................................ 312
18.1 INTRODUCTION
Dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT), and norepinephrine (NE) are important
neurotransmitters in the human brain. These neurotransmitters activate postsynaptic and presynap-
tic receptors, and their concentration is regulated by active reuptake into presynaptic terminals by
transporters.
DA and 5-HT receptors are found in multiple subtypes that are divided into subclasses based
on structural and pharmacological similarities. The DA and 5-HT receptors are all putative seven
transmembrane (TM) G protein-coupled receptors (GPCRs) except for the 5-HT
3
receptor, which is
a ligand-gated ion channel regulating the permeability of sodium and potassium ions. Five subtypes
of DA receptors are known and grouped into the D
1
-like receptors (D
1
and D
5
) and the D
2
-like recep-
tors (D
2
, D
3
, and D
4
), whereas 14 subtypes of 5-HT receptors are known and grouped into seven
subclasses, namely 5-HT
1
(5-HT
1A
, 5-HT
1B
, 5-HT
1D
, 5-HT
1E
, and 5-HT
1F
), 5-HT
2
(5-HT
2A
, 5-HT
2B
,
and 5-HT
2C
), 5-HT
3
, 5-HT
4
, 5-HT
5
(5-HT
5A
and 5-HT
5B
), 5-HT
6
, and 5-HT
7
. In addition, a variety
of polymorphic and splice variants (functional and nonfunctional) have been described for subtypes
of both DA and 5-HT receptors.
Transporters for DA (DAT), 5-HT (SERT), and NE (NET) belong to the same family, the so-
called solute carrier 6 (SLC6) gene family of ion-coupled plasma membrane cotransporters. These
transporters are able to transport DA, 5-HT, and/or NE from the synapse and into the cell using the
sodium gradient. They are not specii c for their substrates, and NET is, for example, important for
the transport/clearance of DA in the cortex. This also i ts with the fact that the highest homology
among the cloned human transporters is found between DAT and NET. Recently, a high-resolution
crystal structure of a bacterial homolog (LeuT
Aa
) of these transporters was published revealing a
dimeric protein with each of the protomers being a 12 TM spanning protein in a unique fold. Thus,
299
