Advisor

David H. Peyton

Date of Award

Summer 7-19-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Chemistry

Department

Chemistry

Physical Description

1 online resource (xiii, 235 pages)

Subjects

Methamphetamine abuse -- Treatment, Biogenic amines -- Receptors, Drug targeting -- Research

DOI

10.15760/etd.1109

Abstract

As a part of the overall program in the Grandy laboratory at Oregon Health & Science University (OHSU), studying the underlying chemical biology of methamphetamine (Meth) addiction, this dissertation reports on the development of six new thyronamine analogs which were synthesized and assayed against trace amine associated receptor 1 (TAAR1), giving preliminary results consistent with the analogs being inverse agonists. Due to highly variable TAAR1 expression levels in the assays, based on inter-assay response to control Meth stimulation as well as other possible factors, kinetic models were developed to qualitatively explain the assay results. The models set approximate limits on the analogs' binding and disassociation rates relative to those of Meth. Analysis of the assays also provides more evidence of TAAR1's basal activity. Based on the models, the conversion rate of ligand-free inactive TAAR1 to ligand-free active TAAR1 is less than 6% of the binding rate of Meth to TAAR1. The models also suggest that the inverse agonists bind to the inactive ligand-free form of TAAR1 between 10 and 100 times faster than Meth binds to the inactive ligand-free form of TAAR1. Three of the new analogs, G5-110s8, G5-112s5, and G5-114s5, bind to the ligand-free active form of TAAR1 faster than they bind to the inactive ligand-free form of TAAR1. The models do not suggest an upper limit on the binding rate of those 3 analogs to the ligand-free active form of TAAR1. A control assay lacking TAAR1 revealed an electrophysiological off-target effect caused by G5-109s8. Also, a novel synthetic route was developed for ET-92, the lead compound for this project, which reduced the number of synthetic steps from 14 to 5 and improved the overall yield from 15.3% to 18.3% (77.4 mg) with the hope that further improvements in yield are possible.

Persistent Identifier

http://archives.pdx.edu/ds/psu/12936

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