Characteristics of iodinated beta-adrenoceptor antagonist ligands in brain.

Willcocks, Alan Leslie (1987). Characteristics of iodinated beta-adrenoceptor antagonist ligands in brain. MPhil thesis The Open University.



This thesis describes several interactions of radiolabelled beta-adrenoceptor antagonists with membranes from cerebral tissue of the rat using ligand binding methods.

Using tritiated ligands and displacement of the binding with selective beta-adrenoceptor agents (distinguishing between β1- and β2- adrenoceptors) it was shown that whilst a mixture of β-adrenoceptor subtypes existed in cerebral cortical membranes - 70%β1 and 30% 70β2- adrenoceptors; only β2-adrenoceptors could be shown in cerebellar membranes.

When a repeat of these experiments was performed using the 125 iodinated ligand I-Iodohydroxybenzylpindolol similar data could not be produced because of a high level of non-specific binding — about 70% of the total at 70 pM 125 I-Iodohydroxybenzylpindolol in cerebral cortical membranes, the α-adrenoceptor antagonists Phentolamine although reported to be effective in lowering this non-specific binding also reduced specific binding 40% at 100μM, however it was susceptible to low centrations of 5-Hydroxytryptamine (5.HT) and its congeners, 5.HT has an IC50 of 7μM, further isomers of Propranolol exhibited about a 10-fold stereoselectivity at these sites suggesting the labelling of a 5-Hydroxytryptamine receptor.

Another iodinated derivative of Pindolol, 125 I-Iodocyanopindolol also demonstrated an ability to associate with 5.HT like sites in cerebral cortical membranes in the absence of ascorbic acid at 1.1 mM , but 125 I-Iodopindolol appeared devoid of this activity associating solely with β-adrenoceptors.

The interaction of β-adrenoceptor antagonists with biochemical models of 5-Hydroxytryptamine receptors - 5.HT1 (35.HT labelling) and 5.HT2(3H-Spiperone labelling) was also investigated. Isomers of Propranolol, Alprenolol and Pindolol all demonstrated stereoselectivity at 5.HT1 but not 5.HT2 receptors, each isomeric pair demonstrating around 100-fold stereoselectivity, on the other hand these compounds were not stereoselective at 5.HT2 sites, the (-)-isomers were less potent. (-)-Pindolol demonstrates a 2,000-fold higher affinity for 5.HT1, over 5.HT2 receptors. Selective β-adrenoceptor antagonists however only weakly displaced binding at either receptor with IC50's between 10 and 100 μM , their affinities here appear unrelated to their beta-adrenoceptor antagonist potency. These results are discussed in terms of behavioural models of 5.HT receptor function.

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