Distinct molecular recognition of psychostimulants by human and Drosophila serotonin transporters

David L Roman; Shannon N Saldaña; David E Nichols; F Ivy Carroll; Eric L Barker

doi:10.1124/jpet.103.057836

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Distinct molecular recognition of psychostimulants by human and Drosophila serotonin transporters

Journal article

Peer reviewed

Distinct molecular recognition of psychostimulants by human and Drosophila serotonin transporters

David L Roman, Shannon N Saldaña, David E Nichols, F Ivy Carroll and Eric L Barker

The Journal of pharmacology and experimental therapeutics, Vol.308(2), pp.679-687

02/2004

DOI: 10.1124/jpet.103.057836

PMID: 14593087

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Abstract

In this study, human embryonic kidney (HEK)-293 cells stably expressing human, Drosophila, or a chimeric serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, dSERT, and H(1-281)D(282-476)H(477-638), respectively) were used to explore the ability of two libraries of structurally distinct psychostimulants to inhibit 5-HT uptake. One library consisted of 3-phenyltropane analogs, whereas the second library consisted of several substituted amphetamines. hSERT exhibited a lower K(i) value for all the compounds in both libraries compared with dSERT, whereas the chimeric SERT exhibited properties more closely resembling those of dSERT. This species selectivity was explored using computer-generated comparative molecular field analysis to model the interactions of the cocaine analogs and substituted amphetamines at hSERT, dSERT, and the cross-species chimera. Models for the 3-phenyltropane analogs indicate that a region exists around the aromatic ring where decreased electron density is favored, particularly for hSERT. This finding may indicate pi-pi stacking with an aromatic amino acid residue in SERT. Also, electronegative substituents in the 4'-position provide favorable interactions. This structural feature was demonstrated by increased potency of analogs with electronegative substituents on the aromatic ring that withdraw electron density. For the substituted amphetamines, key areas for interaction exist around the amine, an electrostatic component surrounding the 3-position on the aromatic ring, and a steric component surrounding the 4-position.

Amphetamines - chemistry

Cell Line

Drosophila Proteins

Membrane Glycoproteins - metabolism

Species Specificity

Drosophila

Humans

Tritium

Nerve Tissue Proteins

Serotonin - chemistry

Serotonin Plasma Membrane Transport Proteins

Structure-Activity Relationship

Recombinant Fusion Proteins - metabolism

Membrane Glycoproteins - genetics

Carrier Proteins - genetics

Animals

Carrier Proteins - metabolism

Amphetamines - metabolism

Membrane Transport Proteins

Serotonin - metabolism

Insect Proteins - metabolism

Details

Title: Subtitle: Distinct molecular recognition of psychostimulants by human and Drosophila serotonin transporters
Creators: David L Roman - Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907-2091, USA
Shannon N Saldaña
David E Nichols
F Ivy Carroll
Eric L Barker
Resource Type: Journal article
Publication Details: The Journal of pharmacology and experimental therapeutics, Vol.308(2), pp.679-687
Publisher: United States
DOI: 10.1124/jpet.103.057836
PMID: 14593087
ISSN: 0022-3565
eISSN: 1521-0103
Grant note: DA05477 / NIDA NIH HHS MH60221 / NIMH NIH HHS
Language: English
Date published: 02/2004
Academic Unit: Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984070587102771

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