Effect of the replacement of the o-methoxyphenyl moiety with nitrogen-containing aromatic rings within N-phenyl-piperazine and phenoxy-ethylamine-based 1,3-dioxo/oxathio/dithiolanes as α1 and 5-HT1A receptor ligands

In the present work, nineteen analogues of 1-[(2,2-Diphenyl-1,3-dioxolan-4-yl)methyl]-4-(2-methoxyphenyl)piperazine 5 and N-[2-(2-Methoxyphenoxy)ethyl]-2,2-diphenyl-1,3-dioxolane-4-methanamine 18 were synthesized. The compounds were tested for binding affinity at 5-HT1AR and α1-AR subtypes. They were also tested using functional assays as α1-AR antagonists and the most promising were tested for functional activity at 5-HT1AR, where they were shown to behave as agonists. The results highlight that the replacement of the 1,3-dioxolane ring with a 1,3-oxathiolane or a 1,3-dithiolane moiety leads to an overall reduction in in-vitro affinity at the α1-AR, while affinity, potency and efficacy were strongly enhanced at the 5-HT1A receptor. Overall, the nitrogen-containing aromatic moieties scarcely affect the affinity at the 5-HT1A receptor, while reducing potency and increasing efficacy. The oxidation of the sulphur atom in the 1,3-oxathiolane to give sulfoxides and solfones has a negative effect on affinity and potency at both receptor systems. Regardless of the effect on the other parameters, selectivity toward 5-HT1AR with respect to the α1-AR is often favoured, but never the contrary. The most striking result is the inversion of selectivity. In fact, while the lead 5 is 100-fold selective for α1-AR, the new derivatives, although to differing degrees, are selective for 5-HT1AR.