Volinanserin


Volinanserin is a highly selective 5-HT2A receptor antagonist that is frequently used in scientific research to investigate the function of the 5-HT2A receptor. It was also tested in clinical trials as a potential antipsychotic, antidepressant, and treatment for insomnia but was never marketed. The drug reached phase 3 trials for schizophrenia and insomnia prior to the discontinuation of its development in the late 2000s. It is taken orally.

Pharmacology

Pharmacokinetics

The time to peak levels of volinanserin is 1 to 2.5hours. The elimination half-life of volinanserin is 6.6hours, with a range of 4.5 to 9.8hours. However, cortical serotonin 5-HT2A receptor occupancy with volinanserin measured by positron emission tomography imaging lasts much longer than its circulating elimination half-life would imply.

Chemistry

Synthesis

The synthesis of volinanserin has been reported. Beginning with protection of ethyl isonipecotate with Boc anhydride gives ethyl N-Boc-4-piperidinecarboxylate. Ester-amide interchange with N-methoxymethylamine HCl in the presence of carbonyldiimidazole coupling agent gives 1-Boc-4-piperidine. Weinreb ketone synthesis occurs upon benzoylation with 1,2-dimethoxybenzene to give 1-Boc-4-piperidine. Acid removal of the urethane protecting group gives -piperidin-4-ylmethanone. The reduction of the ketone with sodium borohydride leads to -piperidin-4-ylmethanol. Resolution of the alcohol gives. SN2 alkylation of the secondary nitrogen with 4-fluorophenethyl bromide completes the synthesis of volinanserin.