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Bioorg Med Chem. 2008 Aug 1;16(15):7415-23. doi: 10.1016/j.bmc.2008.06.009. Epub 2008 Jun 13.

Structure-activity correlations for beta-phenethylamines at human trace amine receptor 1.

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Center for Organic and Medicinal Chemistry, RTI International, 3040 Cornwallis Road, PO Box 12194, Research Triangle Park, NC 27709-2194, USA.


A cell line in which RD-HGA16 cells were stably transfected with the hTAAR 1 receptor was created and utilized to carry out a systematic evaluation of a series of beta-phenethylamines. Fair agreement was observed with data obtained for aryl and ethylene chain substituted analogs in an AV12-664 cell line in which hemagglutinin-tagged hTAAR 1 was stably co-expressed with rat G alpha(s). Analogs with multiple substituents as well as analogs with bulky groups were found to be partial agonists. Analogs in which the primary amino group was converted to a secondary or a tertiary amino group by N-methylation were also partial agonists. Comparative Molecular Field Analysis (CoMFA) using the potency data yielded a regression coefficient r(2) of 0.824. The steric field contribution to the model was 61% with the balance (39%) contributed by the electrostatic field. The collective results suggest that increasing steric bulk both at the amino nitrogen, particularly by N-dimethylation, and at the 4-position of the aromatic ring leads to low efficacy ligands.

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