The synthesis of various substituted 3-amino-7-hydroxy-2,2-dimethyltetralins and their opioid-related activities

Author

David Alan Lippman, University of the Pacific

Date of Award

1984

Document Type

Thesis

Degree Name

Master of Science (M.S.)

Department

Graduate School

First Advisor

Davis S. Fries

First Committee Member

Donald Y. Shirachi

Second Committee Member

Carl E. Wulfman

Third Committee Member

Francis Sayre

Fourth Committee Member

Charles M. Roscoe

Abstract

A series of aminotetralones and aminotetralins were synthesized from the common intermediate F, 3-amino-2,2-dimethyl-7-methoxy- 1-tetralone. The final compounds derived from F were simple substituted and/or reduced analogues. The products would allow a progressive structure activity relationship to be drawn based on pharmacological testing.

The common intermediate F was synthesized utilizing a six step procedure starting with p-methoxyphenylacetic acid. The overall yield from the precursor to the F:HC1 was 25%. Compound F was either O-demethylated to form 3-amino-2,2-dimethyl-7-hydroxy-l-tetralone (I) or was dimethylated on the amine and subsequently O-demethylated to yield the 3-dimethylamino-7-hydroxy-2,2-dimethyl-l-tetralone (J). The last major modification was the reduction of the carbonyl group in J to a methylene, to produce the 3-dimethylamino-7-hydroxy-2,2-dimethyltetralin (L). These final compounds I, J, and L, as well as the intermediates leading to them (compounds F, II, G, and K), were tested for opioid activity in the isolated guinea pig ileum assay as described by Kosterlitz.

All of the compounds exhibited agonist activity. They generally fell into three groups. Compound J was the most potent, giving 1/40 the potency of normorphine (NM). The majority of compounds (F, H, K, and L) were of intermediate potency, ranging in activity from 1/500 to 1/700 the potency of NM. The last two compounds I and G were not only the least potent at 1/2000 to 1/5000 that of NM, but also the least efficacious. In evaluation of the receptor selectivity of the compounds synthesized, a range of selectivity was observed. Compound J was the only compound which appeared to exhibit 100% of its activity through the mu receptor. The other compounds had varying degrees of mixed receptor agonism.

Pages

81

Recommended Citation

Lippman, David Alan. (1984). The synthesis of various substituted 3-amino-7-hydroxy-2,2-dimethyltetralins and their opioid-related activities. University of the Pacific, Thesis. https://scholarlycommons.pacific.edu/uop_etds/2102