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Title: Opiate receptor mechanisms : an in vitro analysis
Author: Leslie, Frances M.
ISNI:       0000 0001 3608 3627
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1977
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The agonist and antagonist properties of narcotic analgesic drugs were examined in the mouse isolated vas deferens. The receptor characteristics of this preparation were then compared with those of other morphine-sensitive tissues. In general, the receptors appeared to resemble those of the guinea-pig isolated ileum, although minor differences were noted. There was a good correlation between the relative agonist potencies of both morphine-like and dual-action compounds in the two peripheral tissues. Dual-action compounds did, however, exhibit flat dose-response curves in the moxise vas deferens, and it was necessary to take special precautions in order to determine their true agonist activities in this preparation. The Ke values of naloxone, and other pure antagonists, to antagonise the actions of normorphine, agreed with those obtained in the ileum within a factor of 2. On the other hand, the antagonist potencies of dual-action compounds were significantly lower in 'the mouse vas deferens. An assessment was made of a new group of benzomorphan agonists which are unusual in that they do not produce a morphine-like dependence syndrome in monkeys. The relative agonist potencies of these compounds were considerably lower in the mouse vas deferens than in the guinea-pig ileum. Furthermore, they required 3 to 5 times more naloxone to antagonise their agonist actions than did morphine-like compounds. The mouse vas deferens was found to be a good predictive model of the clinical analgesic and antagonist activities of opiate drugs. In addition, there was a close relationship between the relative receptor affinities of 'non-dependence producing' benzo-morphans, as measured by inhibition of 3H-dihydromorphine binding to membrane fragments of rat brain, and their relative agonist activities in this isolated preparation. These observations suggest that there is a certain similarity between the receptor populations of brain and vas deferens. The rates of onset and decline of the actions of morphine-like agonists were inversely related to their lipid solubility; this effect may result from secondary binding at lipid-rich sites. Ho relationship was found between drug potency and lipid solubility. These findings are in agreement with those obtained in guinea-pig ileum, but contrast with those obtained in vivo. As an assay preparation, the mouse vas deferens is less robust and consistent in its responses than the guinea-pig ileum. This tissue does, however, exhibit certain features, in particular a high sensitivity to the antagonist properties of dual-action compounds, which make it an invaluable supplementary test system for determining opiate activity. Competitive affinity studies were undertaken in order to compare the binding characteristics of morphine-like and 'non-dependence producing' agonists in guinea-pig brain, ileum and mouse vas deferens homogenates. Comparative analysis of the "binding properties of brain and ileum homogenatss indicated that the receptors being monitored in these preparations were virtually identical in nature. The receptor affinity of each test compound, as measured by 3 inhibition of 3H-naloxone binding, was markedly reduced in the presence of sodium, 'Non-dependence producing' benzomorphans appeared to have lower sensitivities to this inhibitory effect of sodium than did morphine-like agonists. However, a wide variation was found in the sodium shifts of individual morphine-like compounds. Detailed analysis of this sodium effect revealed the existence of a complex relationship between ionic concentration and opiate receptor binding, the sodium' shift of each compound being directly correlated to the slope of the regression line: log IC50 vs log [NaC1]. The Hill coefficients of many of the morphine-like agonists were considerably lower than the theoretical value of unity. This finding suggests that these compounds interact with more than one receptor in order to inhibit the binding of 3H-naloxone. It seems unlikely that these different binding sites represent "sodium" and "no-sodium" conformations of the same receptor. There was a close relationship between the relative receptor affinities of the morphine-like agonists in the absence of sodium, and their relative pharmacological activities in "both the mouse vas deferens and the guinea-pig ileum. In the absence of sodium, the relative activities of the 'non-dependence producing' benzomorphans were similar to their relative agonist potencies in the mouse vas deferens, rather than the guinea-pig ileum. There was a better correlation between the receptor affinities of these compounds and their agonist activities in -!he latter preparation, when binding studies were performed in the presence of 12 mM sodium. Two compounds emerged whose relative potencies to inhibit 3H-naloxone binding, both in the presence and absence of sodium, were considerably lower than their relative agonist potencies in either of the isolated preparations. Of these anomalous compounds, one belonged to the group of morphine-lilce agonists, while the other was a 1non-dependence producing' benzomorphan. The full significance of these findings is discussed, as is the predictive value of competitive affinity studies. Proposals fox future research are outlined.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available