title: Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics.
abstract: OBJECTIVE
  Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies.
  
  
  METHODS
  We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca(2+) i ) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression.
  
  
  RESULTS
  Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca(2+) i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G(670) E).
  
  
  CONCLUSIONS
  The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses.
authors.affiliation: Drug Discovery Biology and Department of Pharmacology, Monash University, Parkville, Vic., Australia.
authors.forename: A E
authors.initials: AE
authors.lastname: Cook
authors.forename: S N
authors.initials: SN
authors.lastname: Mistry
authors.forename: K J
authors.initials: KJ
authors.lastname: Gregory
authors.forename: S G B
authors.initials: SG
authors.lastname: Furness
authors.forename: P M
authors.initials: PM
authors.lastname: Sexton
authors.forename: P J
authors.initials: PJ
authors.lastname: Scammells
authors.forename: A D
authors.initials: AD
authors.lastname: Conigrave
authors.forename: A
authors.initials: A
authors.lastname: Christopoulos
authors.forename: K
authors.initials: K
authors.lastname: Leach
mesh_terms: D000494:Allosteric Regulation; D000814:Aniline Compounds / Q000494:pharmacology; D057966:Calcimimetic Agents / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D000069449:Cinacalcet; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010627:Phenethylamines; D010766:Phosphorylation; D011437:Propylamines; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000378:metabolism*
chemical_list: C506457:(R)-2-(1-(1-naphthyl)ethyl-aminom-ethyl)indole; D000814:Aniline Compounds; D057966:Calcimimetic Agents; D007211:Indoles; D007295:Inositol Phosphates; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D009281:Naphthalenes; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; C002647:inositol 1-phosphate; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium; D000069449:Cinacalcet