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Date of Award

1987

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmacy

First Advisor

Marvin H. Malone

Second Advisor

Katherine A. Taubert

First Committee Member

David S. Fries

Second Committee Member

James W. Blankenship

Third Committee Member

Horace H. Loh

Abstract

Two substituted analogs of 3-amino-2,2-dimethyltetralin, namely 3-dimethylamino-7-hydroxy-2,2-dimethyl-1-tetralone HBr (J) and 3-dimethylamino-7-hydroxy-2,2-dimethyl-1-tetralol (MRSAL) were evaluated for opioid agonist and antagonist activity using the electrically-stimulated guinea pig ileum longitudinal muscle and mouse vas deferens preparations. The effects of these compounds in these tissues were compared to those induced by several opioid prototype agonists at mu, kappa and delta sites (normorphine, dihydromorphine, ethylketocyclazocine, U-50,488H, beta -endorphin, dynorphin 1-13, leu-enkephalin and DADLE) and one opioid antagonist (naloxone). The results of these experiments demonstrated that compound J inhibited contractions in a concentration-dependent manner as an opioid agonist and its effects were antagonized by naloxone in both preparations. The agonist effects of J were also irreversibly antagonized by beta -funaltrexamine pretreatment suggesting a preference for mu receptors. On the other hand, MRSAL was able to antagonize all the opioid agonist prototypes in a concentration-dependent manner, but with varying affinities. The differential opioid receptor selectivity for compound J was studied based on: (i) its agonist potency in guinea pig ileum longitudinal muscle versus the mouse vas deferens; (ii) its irreversible antagonism by beta -funaltrexamine in guinea pig ileum; and (iii) by the calculation of the apparent dissociation constant (Ke) of naloxone for this agonist in both preparations. The opioid receptor preference for MRSAL was based on its potency in antagonizing the opioid agonist prototypes by calculating its Ke value. Based on these criteria, compound J behaved as a mu receptor agonist while MRSAL had preference for mu rather than kappa or delta receptors.

Pages

191

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