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Characterization of highly efficacious allosteric agonists of the human calcium-sensing receptor

Ma, Jian Nong ; Owens, Michelle ; Gustafsson, Magnus LU ; Jensen, Jacob LU ; Tabatabaei, Ali ; Schmelzer, Kara ; Olsson, Roger LU and Burstein, Ethan S. (2011) In Journal of Pharmacology and Experimental Therapeutics 337(1). p.275-284
Abstract

We discovered structurally novel human calcium-sensing receptor (CaSR) allosteric agonists and compared their pharmacology to phenylalkylamine calcimimetics. 1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol (AC-265347) activated CaSR signaling in cellular proliferation and phosphatidylinositol (PI) hydrolysis assays with potencies of 30 and 10 nM, respectively. (S)-1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol) [(S)-AC-265347], the S-enantiomer of AC-265347, was approximately 10- to 20-fold more potent than (R)-1-benzothiazol-2-yl-1-(2, 4-dimethyl-phenyl)-ethanol) [(R)-AC-265347]. The phenylalkylamines cinacalcet and calindol had activity similar to that of AC-265347 in cellular proliferation assays but less activity in PI... (More)

We discovered structurally novel human calcium-sensing receptor (CaSR) allosteric agonists and compared their pharmacology to phenylalkylamine calcimimetics. 1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol (AC-265347) activated CaSR signaling in cellular proliferation and phosphatidylinositol (PI) hydrolysis assays with potencies of 30 and 10 nM, respectively. (S)-1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol) [(S)-AC-265347], the S-enantiomer of AC-265347, was approximately 10- to 20-fold more potent than (R)-1-benzothiazol-2-yl-1-(2, 4-dimethyl-phenyl)-ethanol) [(R)-AC-265347]. The phenylalkylamines cinacalcet and calindol had activity similar to that of AC-265347 in cellular proliferation assays but less activity in PI assays. All compounds had reduced activity when extracellular Ca 2+ was removed, indicating that they cooperate with Ca 2+ to activate CaSRs, and all activated CaSR isoforms with the N-terminal extracellular domain deleted, indicating that they interact with the transmembrane domains. In both cases, AC-265347 and therefore (S)-AC-265347 were significantly more efficacious than the phenylalkylamines. Mutations E837A 7.39 and I841A 7.43 strongly reduced phenylalkylamine-induced signaling, but not AC-265347-or (S)-AC-265347-induced signaling, suggesting different modes of binding. AC-265347 and (S)-AC-265347 stimulated significantly greater responses than cinacalcet or calindol at each of four loss-of-function human polymorphic CaSR variants. AC-265347 did not inhibit the CYP2D6 cytochrome P450 isozyme, unlike cinacalcet, which is a potent CYP2D6 inhibitor. In rats, AC-265347, (S)-AC-265347, and (R)-AC-265347 each reduced serum parathyroid hormone (PTH) with a rank order potency correlated with their in vitro potencies. AC-265347 and (S)-AC-265347 also reduced plasma ionizable calcium ([Ca 2+] o). AC-265347 was orally active, and its plasma concentrations correlated well with its effects on serum PTH. Thus, these highly efficacious CaSR allosteric agonists represent leads for developing therapeutic agents with potential advantages over existing therapies.

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author
publishing date
type
Contribution to journal
publication status
published
in
Journal of Pharmacology and Experimental Therapeutics
volume
337
issue
1
pages
275 - 284
publisher
American Society for Pharmacology and Experimental Therapeutics
external identifiers
  • scopus:79953008685
  • pmid:21239511
ISSN
0022-3565
DOI
10.1124/jpet.110.178194
language
English
LU publication?
no
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ffddb4d5-3937-4dc3-b21a-00ad7cd9f649
date added to LUP
2019-10-02 10:08:16
date last changed
2020-01-08 08:54:57
@article{ffddb4d5-3937-4dc3-b21a-00ad7cd9f649,
  abstract     = {<p>We discovered structurally novel human calcium-sensing receptor (CaSR) allosteric agonists and compared their pharmacology to phenylalkylamine calcimimetics. 1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol (AC-265347) activated CaSR signaling in cellular proliferation and phosphatidylinositol (PI) hydrolysis assays with potencies of 30 and 10 nM, respectively. (S)-1-Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol) [(S)-AC-265347], the S-enantiomer of AC-265347, was approximately 10- to 20-fold more potent than (R)-1-benzothiazol-2-yl-1-(2, 4-dimethyl-phenyl)-ethanol) [(R)-AC-265347]. The phenylalkylamines cinacalcet and calindol had activity similar to that of AC-265347 in cellular proliferation assays but less activity in PI assays. All compounds had reduced activity when extracellular Ca <sup>2+</sup> was removed, indicating that they cooperate with Ca <sup>2+</sup> to activate CaSRs, and all activated CaSR isoforms with the N-terminal extracellular domain deleted, indicating that they interact with the transmembrane domains. In both cases, AC-265347 and therefore (S)-AC-265347 were significantly more efficacious than the phenylalkylamines. Mutations E837A <sup>7.39</sup> and I841A <sup>7.43</sup> strongly reduced phenylalkylamine-induced signaling, but not AC-265347-or (S)-AC-265347-induced signaling, suggesting different modes of binding. AC-265347 and (S)-AC-265347 stimulated significantly greater responses than cinacalcet or calindol at each of four loss-of-function human polymorphic CaSR variants. AC-265347 did not inhibit the CYP2D6 cytochrome P450 isozyme, unlike cinacalcet, which is a potent CYP2D6 inhibitor. In rats, AC-265347, (S)-AC-265347, and (R)-AC-265347 each reduced serum parathyroid hormone (PTH) with a rank order potency correlated with their in vitro potencies. AC-265347 and (S)-AC-265347 also reduced plasma ionizable calcium ([Ca <sup>2+</sup>] <sub>o</sub>). AC-265347 was orally active, and its plasma concentrations correlated well with its effects on serum PTH. Thus, these highly efficacious CaSR allosteric agonists represent leads for developing therapeutic agents with potential advantages over existing therapies.</p>},
  author       = {Ma, Jian Nong and Owens, Michelle and Gustafsson, Magnus and Jensen, Jacob and Tabatabaei, Ali and Schmelzer, Kara and Olsson, Roger and Burstein, Ethan S.},
  issn         = {0022-3565},
  language     = {eng},
  month        = {04},
  number       = {1},
  pages        = {275--284},
  publisher    = {American Society for Pharmacology and Experimental Therapeutics},
  series       = {Journal of Pharmacology and Experimental Therapeutics},
  title        = {Characterization of highly efficacious allosteric agonists of the human calcium-sensing receptor},
  url          = {http://dx.doi.org/10.1124/jpet.110.178194},
  doi          = {10.1124/jpet.110.178194},
  volume       = {337},
  year         = {2011},
}