Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders

PLoS One. 2017 Jul 26;12(7):e0180319. doi: 10.1371/journal.pone.0180319. eCollection 2017.


The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

MeSH terms

  • Adrenergic beta-1 Receptor Agonists / chemistry
  • Adrenergic beta-1 Receptor Agonists / pharmacokinetics
  • Adrenergic beta-1 Receptor Agonists / therapeutic use*
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Animals
  • Brain / metabolism*
  • CHO Cells
  • Cell Line, Tumor
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Drug Discovery
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice, Inbred C57BL
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Neurocognitive Disorders / drug therapy*
  • Neurocognitive Disorders / metabolism
  • Permeability
  • Phenyl Ethers / chemistry
  • Phenyl Ethers / pharmacokinetics
  • Phenyl Ethers / therapeutic use
  • Propanolamines / chemistry
  • Propanolamines / pharmacokinetics
  • Propanolamines / therapeutic use
  • Protein Binding
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta-1 / chemistry
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Structure-Activity Relationship


  • ADRB1 protein, human
  • Adrenergic beta-1 Receptor Agonists
  • Phenyl Ethers
  • Propanolamines
  • Receptors, Adrenergic, beta-1
  • STD-101-D1
  • GTP-Binding Proteins