Theoretical investigations into some drug-receptor interactions.

This study investigates some interactions of agonists with the adrenergic receptor using theoretical and computational chemistry methods. In Chapter 1, the effect of ring fluorination of noradrenaline on the specificity for the a and B receptor is considered. Using a simple receptor model, a conformational difference is found which can explain the experimental observations. In Chapter 2, various theoretical methods are applied to clonidine and a series of similar compounds. The results of these calculations are compared with the differing affinity and activity of these compounds with the adrenergic receptor. Although no correlations are found, it is suggested that these molecules may interact via a charge-transfer interaction, and thus the energies of molecular orbitals such as the HOMO and LUMO may be important in determining activity. In Chapter 3, several molecular orbital procedures are applied to the series of clonidine-like imidazolidines, as well as other series of molecules, to find a method best suited to calculating the energies of molecular orbitals. It is shown that the STO-3G molecular orbital method can be used to calculate a value of the energy of the HOMO which gives a good correlation with the pKa for several series of compounds, hence this method is chosen to calculate the molecular orbital methods of the clonidine series of molecules. The relationship between the activity of clonidine-like imidazolidines and molecular orbital energies is studied in Chapter 4. Several other parameters are also included in the regression equation, but it is shown that the activity of these compounds correlates well with the energy of the LUMO. This suggests that a charge transfer interaction does take place between the az-adrenergic receptor and the agonist. The sequence and some secondary structure information for the Bz- adrenergic receptor is published and, in Chapter 5, a possible agonist binding site is identified using the information gained from the previous chapters. Molecular modelling techniques are successfully used to dock noradrenaline into this site