Structure-activity correlations for beta-phenethylamines at human trace amine receptor 1.
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.
Lewin
Anita H
AH
Center for Organic and Medicinal Chemistry, RTI International, 3040 Cornwallis Road, PO Box 12194, Research Triangle Park, NC 27709-2194, USA. ahl@rti.org
Navarro
Hernán A
HA
Mascarella
S Wayne
SW
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D006801:Humans; D008958:Models, Molecular; D010627:Phenethylamines / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000095383:Trace Amine-Associated Receptors
D010627:Phenethylamines; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors