Autosomal dominant hypocalcemia(ADH)type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants.The calcium-sensing receptor(CaSR)is a class C GPCR that responds to elevated extracellular cal...Autosomal dominant hypocalcemia(ADH)type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants.The calcium-sensing receptor(CaSR)is a class C GPCR that responds to elevated extracellular calcium(Ca^(2+)o)by inhibiting parathyroid hormone(PTH)secretion and promoting renal excretion of Ca^(2+)and other salts to restore physiologically normal Ca^(2+)o concentrations.CaSR negative allosteric modulators(NAMs)transiently raise PTH levels in individuals with ADH1,restoring Ca^(2+)o concentration to a physiological normal range.Herein we disclose the discovery of a chemoreactive NAM(ATF936-NCS,4)for the CaSR that(i)is wash-resistant indicative of irreversible receptor binding and(ii)stimulates prolonged PTH release in vivo.This‘first-in-class’chemical probe will provide invaluable insight towards the development of longer acting NAMs for the treatment of ADH.展开更多
基金supported by the Australian Research Council(No.DP170104228)the National Health and Medical Research Council of Australia(No.1138891)+1 种基金KL and KJG are Australian Research Council Future Fellows(fellowships FT160100075 and FT170100392,respectively)TMJ is a National Health and Medical Research Council Emerging Leader Fellow(fellowship 2008341,Australia).
文摘Autosomal dominant hypocalcemia(ADH)type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants.The calcium-sensing receptor(CaSR)is a class C GPCR that responds to elevated extracellular calcium(Ca^(2+)o)by inhibiting parathyroid hormone(PTH)secretion and promoting renal excretion of Ca^(2+)and other salts to restore physiologically normal Ca^(2+)o concentrations.CaSR negative allosteric modulators(NAMs)transiently raise PTH levels in individuals with ADH1,restoring Ca^(2+)o concentration to a physiological normal range.Herein we disclose the discovery of a chemoreactive NAM(ATF936-NCS,4)for the CaSR that(i)is wash-resistant indicative of irreversible receptor binding and(ii)stimulates prolonged PTH release in vivo.This‘first-in-class’chemical probe will provide invaluable insight towards the development of longer acting NAMs for the treatment of ADH.
