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Date of Award


Document Type


Degree Name

Doctor of Philosophy (Ph.D.)


Graduate School

First Advisor

David Fries

First Committee Member

Alice Jean Matuszak

Second Committee Member

Madhukar G. Chaubal

Third Committee Member

James Blankenshio

Fourth Committee Member

Donald Wedegaertner


Cis and trans isomers of 3-(mono- or dialkylamino)-7-(methoxy or hydroxy)-1-phenyl-1,2,3,4-tetrahydronapthalenes were synthesized. Compounds HC- 11 (cis) and HT- 11 (trans) with 3- (dimethylamino) and 7-methoxy substituents and compounds HC- 13 and HT- 13 with 3- ((cyclopropylmethyl)methylamino) and 7-methoxy substituents were synthesized from their corresponding 3-(methylamino) and 7-methoxy derivatives (HC- 10 and HT- 10). HC- 10 and HT- 10 were previously prepared by reductive amination of the 3-tetralone and separated by fractional recrystallization. HC- 10 was obtained predominantly in a 9:1 ratio. Analysis of proton NMR spectral data supports the fact that both the phenyl group at C-1 and nitrogen substituents at C-3 of the tetralin ring are placed pseudoequatorially in the preferred conformation for the cis and trans isomers. Compounds HC- 10 - 12 and HT- 10 and 11 and also HC- and HT- 13 and 14 were tested for their opioid-related agonist and/or mixed agonist-antagonist properties in the guinea pig ileum (GPI) longitudinal muscle assay as described by Kosterlitz.$\sp{64}$ These tests show that compounds HC- 10 and HC- 11 have agonist activity approaching that for a full agonist but at a higher dose level (approximately $60 \times)$ that for Normorphine (NM). Compounds HC- 13 and HT- 10 were of intermediate potency ranging in activity from 1/300 to 1/700 the potency of NM. Their activities are classified as those of partial agonist. The 0-demethylated compounds HC- 12, HC- 14 and HT- 14 were weak in potencies as agonist. Compounds HT- 11 and HT- 13 were inactive. Agonist activity in these compounds resides predominantly in the cis isomers as revealed by the superior potencies of HC- 10, HC- 11, HC- 13 and HC- 14 over their trans counterparts. This observation is in agreement with those reported earlier$\sp{6}$ for the nonphenolic congeners 2C and 2T. Naloxone (Nx) only partially blocks the activity of these compounds, thus the activity seen on the GPI may not be totally opioid in nature. Antagonism of NM activity by HC- 14 and HT- 14, with pA$\sb 2$ values of 4.9 and 4.63 respectively, shows that these compounds possess little mu receptor antagonist activity. ftn$\sp{6,64}$Please see dissertation for references.