Hexacyclododecylamines with Sigma-1 receptor affinity and calcium channel modulating ability
Van Dyk, Sandra
Geldenhuys, Werner J.
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Introduction: Recent research points to the Sigma Receptor (σR) as a possible neuromodulatory system with multi-functional action and σ1Rs have been suggested as a drug target for a number of CNS conditions. Hexacyclododecylamines have shown σ1R activity and provide an advantageous scaffold for drug design that can improve the blood-brain barrier permeability of privileged structures. Methods and Materials: A series of oxa- and aza- hexaxcyclododecylamines were synthesised and evaluated for sigma-1 receptor activity and voltage-gated calcium channel blocking ability to determine the effect of inclusion of amine containing heterocycles. Results & Discussion: The compounds had promising σ1R activities (Ki = 0.067 – 11.86 µM) with the aza-hexacyclododecylamines 12, 24 and 27 showing some of the highest affinities (Ki = 0.067 µM, 0.215 µM and 0.496 µM respectively). This confirms, as observed in previous studies, that the aza compounds are more favourable for σ1R binding than their oxa counterparts. The addition of the amine heterocycle showed affinities similar to that of related structures with only two lipophilic binding regions. This indicates that the inclusion of an amine heterocycle into these structures is a viable option in the design of new σ1R ligands. Significant voltage-gated calcium channel blocking ability was also observed for 12, 24 and 27, suggesting a link between σ1R activity and intracellular calcium levels. Conclusion: The σ1R activity and potential effect on other receptor classes and calcium channels could prove beneficial in pharmacological application
- Faculty of Health Sciences