Adenosine A2AR/A1R Antagonists Enabling Additional H3R Antagonism for the Treatment of Parkinson's Disease

J Med Chem. 2021 Jun 24;64(12):8246-8262. doi: 10.1021/acs.jmedchem.0c00914. Epub 2021 Jun 9.

Abstract

Adenosine A1/A2A receptors (A1R/A2AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H3 receptor (H3R) antagonists in combination with the "caffeine-like effects" of A1R/A2AR antagonists, we designed A1R/A2AR/H3R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H3R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H3R affinities (Ki < 55 nM). Compound 4 (ST-2001, Ki (A1R) = 11.5 nM, Ki (A2AR) = 7.25 nM) and 12 (ST-1992, Ki (A1R) = 11.2 nM, Ki (A2AR) = 4.01 nM) were evaluated in vivo. l-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg-1, i.p. rats). Compound 12 (2 mg kg-1, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A1 Receptor Antagonists / chemical synthesis
  • Adenosine A1 Receptor Antagonists / metabolism
  • Adenosine A1 Receptor Antagonists / therapeutic use*
  • Adenosine A2 Receptor Antagonists / chemical synthesis
  • Adenosine A2 Receptor Antagonists / metabolism
  • Adenosine A2 Receptor Antagonists / therapeutic use*
  • Animals
  • Dyskinesias / drug therapy
  • Histamine H3 Antagonists / chemical synthesis
  • Histamine H3 Antagonists / metabolism
  • Histamine H3 Antagonists / therapeutic use*
  • Humans
  • Levodopa / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Oxidopamine
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / drug therapy*
  • Piperidines / chemical synthesis
  • Piperidines / metabolism
  • Piperidines / therapeutic use
  • Pyrimidines / chemical synthesis
  • Pyrimidines / metabolism
  • Pyrimidines / therapeutic use
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / metabolism
  • Pyrrolidines / therapeutic use
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A2A / metabolism
  • Receptors, Histamine H3 / metabolism
  • Wakefulness / drug effects

Substances

  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists
  • Histamine H3 Antagonists
  • Piperidines
  • Pyrimidines
  • Pyrrolidines
  • Receptor, Adenosine A2A
  • Receptors, Histamine H3
  • Levodopa
  • Oxidopamine