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Discovery and Structure-Activity Relationships of Nociceptin Receptor Partial Agonists That Afford Symptom Ablation in Parkinson's Disease Models.

Abstract：

:A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induced dyskinesias. SAR around the C-3 substituents investigated effects on NOP binding, intrinsic activity, and selectivity and showed that while the C(3)-substituted indoles are selective, high affinity NOP ligands, the steric, polar, and cationic nature of the C-3 substituents affected intrinsic activity to afford partial agonists with a range of efficacies. Compounds 4, 5, and 9 with agonist efficacies between 25% and 35% significantly attenuated motor deficits in the 6-OHDA-hemilesioned rat model of PD. Further, unlike NOP antagonists, which appear to worsen dyskinesia expression, these NOP partial agonists did not attenuate or worsen dyskinesia expression. The NOP partial agonists and their SAR reported here may be useful to develop nondopaminergic treatments for PD.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kamakolanu UG,Meyer ME,Yasuda D,Polgar WE,Marti M,Mercatelli D,Pisanò CA,Brugnoli A,Morari M,Zaveri NT

doi

10.1021/acs.jmedchem.9b02134

subject

Has Abstract

pub_date

2020-03-12 00:00:00

pages

2688-2704

issue

5

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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