Year

2003

Degree Name

Doctor of Philosophy

Department

Department of Chemistry

Abstract

A constitutively active Cys128 Phe mutant of the α1B-adrenoceptor has been shown to not only activate G-protein coupling in the absence of an agonist, but also activate only a single effector pathway (phospholipase C but not phospholipase A2). This suggests that in the case of the α1B-adrenoceptor, a single receptor subtype forms multiple conformations for G-protein interactions that are specific for a particular G-protein/effector pathway. The existence of this receptor opens up possibilities for the specific modulation of the receptor pathway. Specifically, the development of small molecule ligands which activate a single active conformer would thus provide new signalling-specific therapeutics with pharmacological diversity.

In order to achieve this, ligands which bound selectively to the Cys128Phe mutant α1B-adrenoceptor over the wild-type α1B-adrenoceptor were required. Through molecular modelling studies and pharmacophore development a range of conformationally restrained target ligands have been developed which mimic varying conformations of the endogenous ligand adrenaline. This range of target ligands included a simple cyclic series, a bicyclic series, a spirocyclic series and a spiro-fused series. Members of the bicyclic and spirocyclic series were predicted to have particular selectivity potential for the Cys128Phe mutant α1B-adrenoceptor.

The synthesis of the simple cyclic derivatives was via pynolidinone and piperidone frameworks. A series of nine new bicyclic tropane-based target derivatives were prepared from 6-hydroxytropinone. The major step in the approach to the synthesis of the spirocyclic target ligands was a pro spirocycle-forming intramolecular palladium-assisted cyclisation. One such spirocyclic compound was made. The synthetic procedure for the spiro-fused target derivatives also began from pynolidinone and piperidone frameworks, involving the formation of a hydroxymethyl aryliodide derivative, and a crucial palladium-catalysed intramolecular cyclisation. While this last approach was not completed, a novel indeno-pynole derivative was prepared.

Pharmacological testing of the synthesised simple cyclic and bicyclic derivatives indicated that whilst some of the simple cyclic ligands exhibited selectivity for the Cys128Phe mutant α1B-adrenoceptor, the bicyclic ligands displayed no selectivity for this mutant receptor, and had only weak affinity for both α1B-adrenoceptors. The increased rigidity and steric bulk of the bicyclic ligands appeared not to be favourable. However, the set of bicyclic ligands have provided a promising new lead for selective αID-adrenoceptor ligands.

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