Simultaneous 5-HT1BR agonist/5-HT6R antagonist action as a potential treatment of Parkinson’s disease and its comorbidities

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-HT 1B R and 5-HT 6 R blockade as a putative therapeutic option for PD treatment. We have developed PZKKN-94, a dual h5-HT 1B R agonist (EC 50 = 39 nM) and h5-HT 6 R antagonist (K B = 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-HT 1B and 5-HT 6 orthologs but not at mouse 5-HT 6 . Therefore, PZKKN-94 was tested in two rat disease models: haloperidol-induced catalepsy and 6-OHDA-induced sensorimotor deficits in rats showing anti-parkinsonian-like effect in both. Of note, PZKKN-94 did not affect 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 reduced dopamine-mimetic medication effects. In addition, PZKKN-94 reversed scopolamine-, phencyclidine-, and aged-induced learning deficits in the rat novel object recognition (NOR) test, increased cognitive flexibility in the attention set shifting task (ASST), and displayed antidepressant-like actions in the forced swim test (FST) in rats. Our data suggest that dual-acting 5-HT 1B R agonists/5-HT 6 R antagonists provide a novel therapeutic approach to alleviate both motor symptoms and accompanying cognitive and depression co-morbidities in PD. Our present findings highlight the dual 5-HT 1B R agonist/5-HT 6 R antagonist strategy to simultaneously spare L-DOPA's action and alleviate motor fluctuations related to L-DOPA treatment.