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Vol. 59, Issue 3, 514-523, March 2001
Department of Pharmacology and Center for Molecular Neuroscience,
Vanderbilt University Medical Center, Nashville, Tennessee (E.M.A.,
R.D.B.); and Department of Medicinal Chemistry and Molecular
Pharmacology, Purdue University School of Pharmacy, West Lafayette,
Indiana (E.L.B.)
The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) is
responsible for the inactivation of synaptic 5-HT and is also a target
for multiple psychostimulants. Despite the critical role of SERT in
5-HT inactivation and psychostimulant response, many aspects of the
transporter's recognition of ligands are poorly defined. We took
advantage of sequence divergence of SERT species variants to identify
structural determinants of substrate recognition. Tryptamine
derivatives with substitutions at the 4 and 7 positions on the phenyl
ring, the indole nitrogen, and the 
position show up to
40-fold potency differences for inhibiting [3H]5-HT
transport in cells transfected with either human or Drosophila melanogaster SERT cDNAs. Species selectivities of these
derivatives were largely recapitulated in antagonist binding.
Human/D. melanogaster SERT chimera studies implicated
the first two SERT transmembrane domains (TMDs) in the potency of the
indole nitrogen-substituted compounds
N-isopropyltryptamine (NIT),
5-methoxy-N-isopropyltryptamine (5-MNIT), and the
7-substituted compound 7-benzyloxytryptamine (7BT). Potency differences
of analogs with substitutions at the 4 and positions are
influenced by sequences distal to this region. Within TMD I-II,
species-scanning mutagenesis implicated a single residue (Y95 in human
SERT, F90 in D. melanogaster SERT) in the recognition of
NIT, 5-MNIT, and 7BT. Remarkably, this is the same site we established
previously in species-specific recognition of the antagonists
citalopram and mazindol. These findings support a critical role for TMD
I residues in defining shared aspects of SERT substrate and antagonist recognition.
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