Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: Optimising brain penetration

The optimisation of molecular properties within a series of 2-amino dihydroquinazoline 5-HT5A/5-HT7 receptor ligands resulted in a significantly improved brain-to-plasma ratio, enhancing the pharmacological utility of these compounds. By modulating the lipophilicity and pKa, a 20-fold increase in brain-to-plasma ratio could be achieved, leading to micromolar brain concentrations after oral administration. The enantiomers of one representative of this series of improved compounds were separated, and the configuration of the eutomer was determined by X-ray crystallography.

The optimisation of molecular properties within a series of guanidine-type dual 5-HT5A/5-HT7 receptor ligands led to an improved brain-to-plasma ratio. The best representative of optimised compounds reached micromolar brain concentrations after oral administration.Figure optionsDownload as PowerPoint slide