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 H1–281D282–476H477–638, 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 Ki 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.
Footnotes
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This work was supported by National Institute of Mental Health Grant MH60221 (to E.L.B.) and National Institute on Drug Abuse Grant DA05477 (to F.I.C.).
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DOI: 10.1124/jpet.103.057836.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine, serotonin; SERT, serotonin transporter; CoMFA, comparative molecular field analysis; TMD, transmembrane domain; HEK, human embryonic kidney; KRH, Krebs-Ringer-HEPES; PLS, partial least-squares; DAT, dopamine transporter; NET, norepinephrine transporter, CPT-d-tartrate, (–)-2β-carbomethoxy-3β-phenyltropane tartrate; B-CFT, (–)-2-β-carbomethoxy-3-β-(4-fluorophenyl)-tropane 1,5-naphthalenedisulfonate; RTI-142, (–)-N-nor-3β-(4-fluorophenyl)tropane-2β-carboxylic acid methyl ester; RTI-121, 3β-(4-iodophenyl)-tropane-2β-carboxylic acid isopropyl ester hydrochloride; RTI-55, 3β-(4-iodophenyl)tropane-2β-carboxylic acid methyl ester tartrate; RTI-112, (–)-3β-(3-methyl-4-chlorophenyl)tropane-2β-carboxylic acid methyl ester tartrate; RTI-32, 3β-(4-methylphenyl)tropane-2β-carboxylic acid methyl ester tartrate; RTI-31, 3β-(4-chorophenyl)tropane-2β-carboxylic acid methyl ester tartrate; RTI-83, 3β-(4-ethylphenyl)tropane-2β-carboxylic acid methyl ester tartrate; RTI-311, N-allyl-N-nor-3β-(4-iodophenyl)tropane-2β-carboxylic acid methyl ester tartrate; DCA, 3,4-dichloroamphetamine; 4-MTA, 4-methylthioamphetamine; 2-Me-MDA, 2-methyl-3,4-methylenedioxyamphetamine; MMAI, 5-methoxy-6-methyl-2-aminoindan, MDA, 3,4-methylenedioxyamphetamine; 3-MTA, 3-methylthioamphetamine; AMMI, 1-aminomethyl-5-methoxyindan; DFA, 3,4-difluoroamphetamine; 6-Me-MDA, 6-methyl-3,4-methylenedioxyamphetamine; 4-TFMA, 4-trifluoromethylamphetamine; AMMT, 1-aminomethyl-6-metoxytetralin.
- Received September 3, 2003.
- Accepted October 16, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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