Abstract
MOLECULAR PHARMACOLOGY
Vol. 59, No. 3
Copyright © 2001 The American Society for Pharmacology and Experimental
Therapeutics 547/883038
Mol Pharmacol 59:514–523, 2001 Printed in U.S.A.
Interactions
of Tryptamine Derivatives with Serotonin
Transporter Species Variants Implicate Transmembrane
Domain I in Substrate Recognition
ERIKA M. ADKINS, ERIC
L. BARKER, and RANDY D. BLAKELY
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.)
Received September 7, 2000; accepted November 17, 2000 This paper is available
online at http://molpharm.aspetjournals.org
ABSTRACT
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 b 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 b 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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