Discovery of a selective α2C-AR scaffold from a molecular hybridization approach

We undertook the rational design and synthesis of a novel series of ligands intended to function as selective dual dopamine D1 receptor (D1R) partial agonists and D3 receptor (D3R) antagonists. The molecular architecture of these compounds was derived by integrating key pharmacophoric features from established D1R partial agonists and D3R antagonists. Specifically, the 6-(2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione scaffold was employed as the core "tail" region associated with D1R partial agonism, while various substituted phenyl piperazine moieties were introduced as "head" groups to confer D3R antagonistic activity. A pyridine ring was utilized as a central linker across the series. Contrary to the intended dopaminergic profile, these compounds exhibited markedly higher binding affinities for α2-adrenergic receptors (α2-ARs) relative to their activity at dopamine receptor subtypes. Several analogues demonstrated potent α2C-AR binding affinities in the low nanomolar range (K_i = 7-30 nM), with moderate selectivity (up to 17-fold) over other α2-AR subtypes. Notably, compounds bearing ortho-substituted aryl groups within the "head" domain generally displayed enhanced α2C-AR binding compared to their para-substituted counterparts. Molecular docking studies conducted at both α2A-AR and α2C-AR suggested that multiple receptor-ligand interactions contribute to the observed binding profiles. In particular, an anion-pi interaction between Asp131 of α2C-AR and the phenyl ring of the phenyl piperazine "head" moiety was identified as a possible determinant of the increased α2C-AR affinity observed in ortho-substituted analogues. Given the therapeutic potential of selective α2C-AR targeting in treating various disorders, coupled with the limited availability of clinically approved selective α2C-AR ligands, the discovery of this new scaffold offers new prospects for drug discovery targeting α2C-ARs.