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

Date Published: July 26, 2017

Publisher: Public Library of Science

Author(s): Bitna Yi, Alam Jahangir, Andrew K. Evans, Denise Briggs, Kristine Ravina, Jacqueline Ernest, Amir B. Farimani, Wenchao Sun, Jayakumar Rajadas, Michael Green, Evan N. Feinberg, Vijay S. Pande, Mehrdad Shamloo, Vardan Karamyan.


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.

Partial Text

Adrenergic receptors (ADRs) are G protein-coupled receptors (GPCR) that mediate the central and peripheral effects of noradrenaline (NA) and adrenaline [1, 2]. They are widely expressed throughout the body and play an important role in regulating multiple physiological processes including cardiac muscle contraction, airway reactivity, cognition, arousal, stress-related behavior, and inflammation [2–5]. Multiple subtypes of ADRs exist. Each subtype is expressed in distinct patterns and involved in multiple physiological processes [2, 6]. Therefore, ligands that selectively target one subtype will be valuable both as research tools to identify the roles of different ADR subtypes and as potential therapeutic agents for multiple diseases related to dysfunction of the NA and adrenaline systems.

In this study we established SARs for a novel chemotype targeting the ADRB1. The key compound, STD-101-D1, produced partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engaged very little β-arrestin signaling compared to the unbiased agonist isoproterenol. This biased ligand represents a new mode for ADRB1 activation and is distinctly different compared to isoproterenol—a full and unbiased agonist.




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