Year

1999

Degree Name

Doctor of Philosophy

Department

Department of Chemistry

Abstract

The α1-adrenergic receptors (α1-ARs) mediate many effects of the sympathetic nervous system. Like other adrenergic receptors, α1-ARs are activated by the catecholamines, adrenaline and noradrenaline. The α1-ARs are membrane proteins and members of the Gprotein coupled receptor superfamily. Three distinct subtypes have been confirmed by cloning techniques.

The α1-ARs have a divergent affinity for many synthetic drugs. Drugs interacting as agonists and antagonists with the subtypes selectively have been used in the treatment a variety of diseases including hypertension, asthma and prostatic hypertrophy. However, there is still no antagonist available to discriminate between the subtypes by 1000 or more fold.

In order to design such selective antagonists, firstly, ligand based methods have been used by means of Apex-3D and Catalyst software of Molecular Simulations, Inc (MSI). Pharmacophores of the α1A- and α1B-ARs were generated together with a pharmacophore for the α1D-AR. These are the first α1-subtype specific pharmacophores for antagonists reported. Tetrahydroisoquinoline ring-containing compounds were designed, synthesised and tested as ligands on the cloned and expressed human α1-ARs. These results have also been evaluated via other computer-aided techniques, such as molecular electrostatic potential mapping and docking. Secondly, structure-based drug design methods have been developed using Insight software of MSI. New models of α1A- and α1B-adrenoceptors have been built and by the use of docking procedures, more detailed information about the binding pocket in the receptor for the ligands obtained and some modifications on the target compounds have been proposed to design novel ligands with potentially higher activity and selectivity. Finally, these two techniques, ligand-based and structure-based design methods have been brought together to produce a novel approach called docking-derived pharmacophore modelling to create more detailed pharmacophore models for the α1A- and α1B-AR subtypes. The overall results are discussed and future directions proposed.

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