Novel antiparkinsonian Prottremine-based agents containing benzyl- and monoterpene-piperazine fragments

Abstract Parkinson’s disease is a progressive neurodegenerative disorder with an increasing global prevalence, characterized by the loss of dopaminergic neurons. Current treatments, including levodopa and MAO-B inhibitors, provide only symptomatic relief and are associated with significant side effects and declining efficacy. Based on the monoterpenoid Prottremine, an antiparkinsonian agent that has entered clinical trials, a series of piperazine derivatives with benzyl- and monoterpene-fragments was synthesized. The target compounds were obtained in 40–63 % yields and evaluated in MPTP- and haloperidol-induced mouse models of parkinsonism at a 20 mg/kg dose. Several new derivatives showed pronounced antiparkinsonian activity, for example, compounds 6b and 6d containing 4-fluoro- and 4-isopropylbenzyl fragments, increased locomotor activity in the open field test, whereas compounds 6a with an unsubstituted phenyl ring and 6d improved motor coordination in the hanger coat test. Moreover, compounds 6a and 6b reduced haloperidol-induced catalepsy, a model of drug-induced parkinsonism, whereas derivative 6d showed no activity in this test. Also, pharmacological screening revealed that some of the compounds can affect dopaminergic or anticholinergic neurotransmitter systems. The most promising compound 6b exhibited low acute toxicity (well tolerated dose is more than 230 mg/kg). Thus, a set of novel substituted piperazine derivatives of Prottremine was synthesized, with compound 6b emerging as a promising hit for the development of new antiparkinsonian agents.