Synthesis and Biological Evaluation of Rigid Benztropine Analogues with Potential DAT Inhibition Activity: A Prospect...

The pharmacological treatment of Parkinson's, an incurable disease, consists of palliative drug combinations, generally including a Dopamine Transporter (DAT) inhibitor and an exogenous source of dopamine. Benztropine has been described as a commonly used DAT inhibitor. However, the ever-increasing secondary effects led to its substitution with other, more suitable drugs. It has been described that the tropine moiety of the molecule generates most of the interaction with DAT, while other relevant interactions correspond to the benzhydryl aromatic moiety with several degrees of freedom due to the rotation of the phenyl rings.

Through organic chemistry synthesis, NMR, and other techniques, compounds are obtained and then, using in silico analysis, the interaction of DAT and the newly obtained analogs is assessed. Finally, a hemiparkinsonian animal model is generated by 6-OHDA injections and then treated with pharmaceutical concentrations of the main compound, to measure its ability to mitigate symptoms using several behavioral tests.

An eight-member family of fluorenatropines was generated, and compound 9, the simplest of them, was tested in silico to see its direct interaction with DAT. Results suggest a positive and benztropine-like interaction. Behavioral results statistically demonstrated that compound 9 showed activity as a psychostimulant.

Compound 9, with its more rigid structure, behaves as a psychostimulant, mitigating Parkinson's disease symptoms with the same efficiency as benztropine but with a quarter of the original dose.

The rigid aromatic sections in fluorenatropine analogs grant a superior activity over DAT, allowing motor symptom mitigation at lower concentrations.