Simultaneous 5-HT<sub>1B</sub>R agonist/5-HT<sub>6</sub>R antagonist action as a potential treatment of Parkinson's disease and its comorbidities.

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Parkinson's disease (PD) treatment focuses mainly on the augmentation of dopamine transmission, but to alleviate adverse motor effects accompanying L-DOPA use, additional treatments with serotonergic (5-HT) medications may be considered. We propose a novel concept based on the simultaneous activation of 5-HT1BR and 5-HT6R blockade as a putative therapeutic option for PD treatment. We have developed PZKKN-94, a dual human 5-HT1BR agonist (EC50 = 39 nM) and human 5-HT6R antagonist (KB = 7.7 nM), with selectivity over 43 targets, favorable drug-like properties, and brain penetration. Importantly, PZKKN-94 potency was increased or retained at rat 5-HT1B and 5-HT6 orthologs but not at mouse 5-HT6. Therefore, PZKKN-94 was tested in 2 rat disease models: haloperidol-induced catalepsy and 6-hydroxydopamine-induced sensorimotor deficits in rats, showing antiparkinsonian-like effects in both. Of note, PZKKN-94 did not affect the therapeutic effects of L-DOPA and attenuated L-DOPA-induced motor fluctuation ("on-off" phenomena) in the stepping and vibrissae tests. PZKKN-94 had no effect on L-DOPA-induced contralateral rotation, suggesting no impact on dopamine-mimetic medication effects. In addition, PZKKN-94 reversed scopolamine-, phencyclidine-, and aged-induced learning deficits in the rat novel object recognition test, increased cognitive flexibility in the attention set-shifting task, and displayed antidepressant-like actions in the forced swim test in rats. Our data suggest that dual-acting 5-HT1BR agonists/5-HT6R antagonists provide a novel therapeutic approach to alleviate both motor symptoms and accompanying cognitive and depression comorbidities in PD. Our present findings highlight the dual 5-HT1BR agonist/5-HT6R antagonist strategy to simultaneously spare L-DOPA's action and alleviate motor fluctuations related to L-DOPA treatment. SIGNIFICANCE STATEMENT: The commonly used L-DOPA-based medications for Parkinson's disease, though effective in alleviating initial disease states, are limited in long-term use due to the motor (dyskinesia and on-off phenomena) and nonmotor (psychotic-like) side effects. A novel nondopaminergic strategy for treatment of Parkinson's disease based on simultaneous activation of the 5-HT1B receptor and blockade of the 5-HT6 receptor is proposed. The compound PZKKN-94 produces an antiparkinsonian-like effect and attenuates motor fluctuations, preserving the efficacy of L-DOPA. In addition, PZKKN-94 demonstrates procognitive and antidepressant-like properties.

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