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

Discovery of Novel Brain Permeable and G Protein-Biased beta-1 Adrenergic Receptor Partial Agonists for the Treatment of Neurocognitive Disorders

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Discovery of Novel Brain Permeable and G Protein-Biased beta-1 Adrenergic Receptor Partial Agonists for the Treatment of Neurocognitive Disorders

Bitna Yi et al. PLoS One. .
Free PMC article

Abstract

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Structure of (S)-xamoterol and two sites of modification.
Fig 2
Fig 2. Synthesis of (R)- and (S)-xamoterol.
Fig 3
Fig 3. General method for the synthesis of compounds STD-101-B1 to B8.
Fig 4
Fig 4. Synthesis of STD-101-B9.
Fig 5
Fig 5. General method for the synthesis of compounds STD-101-D1 to D6.
Fig 6
Fig 6. Syntheses of the amine components for STD-101-D5 and D6.
Fig 7
Fig 7. Effects of structural modifications of the phenolic OH moiety of xamoterol on the cAMP pathway mediated by ADRB1.
clogPa, Calculated with ChemDraw Pro Version 16.0 (PerkinElmer Health Sciences, CT; EC50 (nM)b, Geometrical mean of EC50 values from at least two independent experiments; % Iso maxc, Percent efficacy compared to the maximum response achieved with isoproterenol; ~d, Could not be determined.
Fig 8
Fig 8. Concentration-response effects of compounds on the cAMP pathway via ADRB1.
Data are expressed as a percentage of maximum efficacy obtained with the full agonist isoproterenol. Values represents means ± S.E.M.s (1–2 experiments with n = 1–2).
Fig 9
Fig 9. Effects of structural modifications of the morpholino urea moiety of xamoterol on the cAMP pathway mediated by ADRB1.
clogPa, Calculated with ChemDraw Pro Version 16.0; EC50 (nM)b, Geometrical mean of EC50 values from at least two independent experiments; % Iso maxc, Percent efficacy compared to the maximum response achieved with isoproterenol; ~d, Could not be determined.
Fig 10
Fig 10. Concentration-response effects of compounds on the β-arrestin pathway via ADRB1.
Data are expressed as a percentage of maximum efficacy obtained with the full agonist isoproterenol. Values represents means ± S.E.M.s (1–2 experiments with n = 1–2). Xamoterola; data has been previously published [11].
Fig 11
Fig 11
Crystal structure of ADRB1 with xamoterol (S) (cyan, panel A), xamoterol (R) (blue, panel B), and STD-101-D1 (salmon, panel C) docked into the ligand-binding site. The transmembrane regions are shown as green ribbons, and. Putative interactions are displayed as yellow dashed lines with estimated distance in angstroms (Å). The carbon-nitrogen chain of xamoterol (S) is predicted to pack approximately 1.0 Angstroms closer to D121 and Transmembrane Helix 3 compared to xamoterol (R), and its morpholino ring rests in a rotated pose as well.
Fig 12
Fig 12. Inhibitory effects of ADRB1 ligands on LPS-induced TNFα response in primary microglia.
Data are represented as mean ± S.E.M.s of four independent experiments (n = 3–18 per group, * p < 0.05, **p < 0.01, *** p < 0.001, one-way ANOVA followed by Dunnett’s multiple comparison against LPS exposure alone).
Fig 13
Fig 13. Inhibitory effects of ADRB1 ligands on LPS-induced TNFα response in mice.
(A) Plasma TNFα concentrations in control animals and animals pretreated with xamoterol or STD-101-D1 90 min after LPS injection. (B) TNFα, IL1β, and IL6 mRNA expression in homogenized cortical tissue from control mice and animals pretreated with xamoterol or STD-101-D1 90 min after LPS injection. Data are represented as mean ± S.E.M.s of three independent experiments. (n = 4–14 per group, * p < 0.05, **p < 0.01, *** p < 0.001, one-way ANOVA followed by Dunnett’s multiple comparison).
Fig 14
Fig 14. Metabolic stability in mouse, rat, and human microsomes.
STD-101-D1 and two reference compounds verapamil and propranolol were incubated at 0.1 uM in mouse (A), rat (B), or human (C) liver microsomes. Serial samples were removed up until 60 min. All experiments were performed in duplicate, and data are represented as mean ± S.E.M.
Fig 15
Fig 15. Pharmacokinetics of xamoterol and STD-101-D1.
Systemic (A) and portal vein (B) plasma concentrations of xamoterol and STD-101-D1 as a function of time after a single injection of xamoterol (10 mg/kg) or STD-101-D1 (10 mg/kg) via intravenous (IV), intraperitoneal (IP) and oral (PO) administration. Plasma and brain (C) concentrations of xamoterol and STD-101-D1 in rats collected 20 min after a single injection of xamoterol or STD-101-D1 (10 mg/kg) via IV, IP, and PO administration. Data are represented as mean ± SEM (n = 3 per route).
Fig 16
Fig 16. Effects of xamoterol and STD-101-D1 on heart rate and blood pressure.
Changes in heart rate (A) and blood pressure (B) following subcutaneous administration of xamoterol or STD-101-D1 at dose of 3 mg/kg. Date are represented as mean ± SEM (n = 3 per compound). (One-sample t-test vs. 0% theoretical mean, * p < 0.05).

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