Design and synthesis of novel alpha1 adrenoceptor modulators

Author

Susan J. McGinty, University of Wollongong

Year

2003

Degree Name

Doctor of Philosophy

Department

Department of Chemistry

Recommended Citation

McGinty, Susan J., Design and synthesis of novel alpha1 adrenoceptor modulators, Doctor of Philosophy thesis, Department of Chemistry, University of Wollongong, 2003. https://ro.uow.edu.au/theses/1129

Abstract

A constitutively active Cys¹²⁸ Phe mutant of the α_1B-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 α_1B-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 α_1B-adrenoceptor over the wild-type α_1B-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 α_1B-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 α_1B-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 α_ID-adrenoceptor ligands.