Faculty Collaboration Database

Simultaneous 5-HT_1BR agonist/5-HT₆R antagonist action as a potential treatment of Parkinson's disease and its comorbidities. J Pharmacol Exp Ther 2025 Feb;392(2):100055

Date

03/03/2025

Pubmed ID

40023605

DOI

10.1016/j.jpet.2024.100055

Scopus ID

2-s2.0-85218008513 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

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_1BR and 5-HT₆R blockade as a putative therapeutic option for PD treatment. We have developed PZKKN-94, a dual human 5-HT_1BR agonist (EC₅₀ = 39 nM) and human 5-HT₆R 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-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-HT_1BR 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-HT_1BR 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-HT_1B 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.

Author List

Zajdel P, Matłoka M, Konieczny J, Kos T, Lammers JC, Cavalco NG, Clark AA, Lenda T, Satała G, Canale V, Grychowska K, Krawczyk M, Nikiforuk A, Partyka A, Jastrzębska-Więsek M, Berghauzen-Maciejewska K, Biała D, Janicka M, Janusz A, Piast R, Mulewski K, Smuga D, Pieczykolan J, Wieczorek M, Moszczyński-Pętkowski R, Dubiel K, Ossowska K, Bojarski AJ, Kamiński K, McCorvy JD, Popik P

Author

John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antiparkinson Agents
Humans
Male
Mice
Oxidopamine
Parkinson Disease
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT1B
Receptors, Serotonin
Serotonin 5-HT1 Receptor Agonists
Serotonin Antagonists