DREADD agonist compound 21 causes acute diuresis in wild-type mice
Bryce MacIver1, Ali Wu1, Warren G Hill1
1Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States.
Frontiers in Pharmacology
|November 8, 2024
Summary
Compound 21 (C21), a designer receptor exclusively activated by designer drugs (DREADD) agonist, unexpectedly caused a significant diuretic effect in mice. This highlights potential off-target effects of C21 on renal and bladder function.
Area of Science:
- Pharmacology
- Nephrology
- Molecular Biology
Background:
- Chemogenetics, particularly Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), enables precise control of cellular functions.
- Compound 21 (C21) is a potent agonist for DREADDs, but its potential off-target binding to endogenous G protein-coupled receptors (GPCRs) requires investigation.
- Understanding renal innervation is crucial for regulating kidney function, and chemogenetics offers new avenues for research.
Purpose of the Study:
- To pharmacologically characterize the effects of Compound 21 (C21) on renal function.
- To investigate potential off-target effects of C21, particularly on GPCRs involved in renal and bladder physiology.
- To assess the suitability of C21 for chemogenetic studies of renal function.
Main Methods:
- Administration of C21 to anesthetized and awake mice.
- Measurement of urine output and glomerular filtration rate (GFR).
- Voiding spot assays to assess bladder function.
- In vitro myography to evaluate C21's effect on bladder smooth muscle contraction and M3 receptor antagonism.
Main Results:
- C21 infusion (1.0 mg/kg) in mice led to a significant increase in urine output (approximately 4-fold) and GFR.
- C21 demonstrated an acute diuretic effect, confirmed in both anesthetized and awake animal models.
- In vitro studies showed C21 antagonizes M3 receptors at micromolar concentrations, inhibiting bladder smooth muscle contraction and increasing voiding volume.
- C21 exhibits dose-dependent off-target effects on the renal system, acting as a GPCR antagonist.
Conclusions:
- Compound 21 (C21) possesses significant off-target effects on the renal and bladder systems, acting as a GPCR antagonist.
- The observed diuretic and bladder effects necessitate careful consideration of C21's dose and potential confounding influences in chemogenetic research.
- Further characterization is required to fully understand the implications of C21's off-target activity for its use in studying renal function.
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