Search for promising antiparkinsonian agents among monoterpene-bearing azaadamantanes

Parkinson’s disease (PD) involves degeneration of nigrostriatal dopaminergic neurons with a consequent imbalance across multiple neurotransmitter systems regulating basal ganglia function. Amantadine (AMD; 1-aminoadamantane) is a low-affinity, uncompetitive NMDA receptor antagonist and a modulator of CNS neurotransmission that alleviates motor symptoms of PD but is limited by modest efficacy. Azaadamantanes bearing a monoterpene moiety are proposed as aminoadamantane analogs with potential to stimulate dopaminergic transmission and antagonize glutamatergic NMDA receptors. Aim of the study was to compare the effects of monoterpene-containing azaadamantanes (K-372, K-818) and AMD on key neurotransmitter systems implicated in PD pathogenesis using validated in vivo models. Material and methods . Male CD-1 and C57BL/6 mice received a single intraperitoneal dose of each agent at 20 mg/kg. Outcomes were measured in the following models: parkinsonism, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), haloperidol-induced catalepsy, arecoline-induced tremor, yohimbine toxicity, and corazole-induced seizures models. Results and discussion . In the MPTP model, K-372 and K-818 significantly improved locomotor and exploratory activity, indicating dopaminergic stimulation, whereas AMD significantly improved only one locomotor endpoint (p<0,05). In haloperidol-induced catalepsy, only K-818 showed significant anticataleptic activity comparable to AMD, whereas K-372 had no effect. In the arecoline tremor assay, K-372 and K-818 prolonged latency and reduced tremor duration more effectively than AMD, suggesting a moderate central antimuscarinic action, while AMD produced no significant effect. In yohimbine toxicity model, K-372 and K-818 decreased animal survival, corresponds to potentiation of adrenergic transmission, whereas AMD showed a modest trend toward lower toxicity. In the corazole model, none of the agents altered seizure latency, indicating no evidence of GABAergic stimulation, which aligns with a mechanism resembling amantadine. Conclusions. K-372 and K-818 demonstrate robust antiparkinsonian activity in the MPTP model and efficacy against muscarinic arecoline-induced tremor in mice, while exhibiting adrenergic potentiation and no signs of GABAergic stimulation.