Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

2018 ◽  
Vol 61 (14) ◽  
pp. 5949-5962 ◽  
Author(s):  
Yoshikazu Nishimura ◽  
Toru Esaki ◽  
Yoshiaki Isshiki ◽  
Naoki Okamoto ◽  
Yoshiyuki Furuta ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Small Molecule ◽  
Hormone Receptor ◽  
Human Parathyroid Hormone ◽  
Parathyroid Hormone Receptor

scholarly journals Actions of the Small Molecule Ligands SW106 and AH-3960 on the Type-1 Parathyroid Hormone Receptor

2015 ◽  
Vol 29 (2) ◽  
pp. 307-321 ◽  
Author(s):  
Percy H. Carter ◽  
Thomas Dean ◽  
Brijesh Bhayana ◽  
Ashok Khatri ◽  
Raj Rajur ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Small Molecule ◽  
Hormone Receptor ◽  
Transmembrane Domain ◽  
Receptor Activation ◽  
Blood Calcium ◽  
Parathyroid Hormone Receptor ◽  
Peptide Analog ◽  
Amino Terminal ◽  
Small Molecule Ligands

Abstract The parathyroid hormone receptor-1 (PTHR1) plays critical roles in regulating blood calcium levels and bone metabolism and is thus of interest for small-molecule ligand development. Of the few small-molecule ligands reported for the PTHR1, most are of low affinity, and none has a well-defined mechanism of action. Here, we show that SW106 and AH-3960, compounds previously identified to act as an antagonist and agonist, respectively, on the PTHR1, each bind to PTHR1-delNT, a PTHR1 construct that lacks the large amino-terminal extracellular domain used for binding endogenous PTH peptide ligands, with the same micromolar affinity with which it binds to the intact PTHR1. SW106 antagonized PTHR1-mediated cAMP signaling induced by the peptide analog, M-PTH(1–11), as well as by the native PTH(1–9) sequence, as tethered to the extracellular end of transmembrane domain (TMD) helix-1 of the receptor. SW106, however, did not function as an inverse agonist on either PTHR1-H223R or PTHR1-T410P, which have activating mutations at the cytoplasmic ends of TMD helices 2 and 6, respectively. The overall data indicate that SW106 and AH-3960 each bind to the PTHR1 TMD region and likely to within an extracellularly exposed area that is occupied by the N-terminal residues of PTH peptides. Additionally, they suggest that the inhibitory effects of SW106 are limited to the extracellular portions of the TMD region that mediate interactions with agonist ligands but do not extend to receptor-activation determinants situated more deeply in the helical bundle. The study helps to elucidate potential mechanisms of small-molecule binding at the PTHR1.

Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist

2020 ◽  
Vol 63 (10) ◽  
pp. 5089-5099 ◽  
Author(s):  
Yoshikazu Nishimura ◽  
Toru Esaki ◽  
Yoshiaki Isshiki ◽  
Yoshiyuki Furuta ◽  
Akemi Mizutani ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Receptor ◽  
Lead Optimization ◽  
Reactive Metabolite ◽  
Human Parathyroid Hormone ◽  
Parathyroid Hormone Receptor

A C-terminally truncated human parathyroid hormone receptor is functional and activates multiple G protiens

FEBS Letters ◽  
1994 ◽  
Vol 355 (2) ◽  
pp. 210-210 ◽  
Author(s):  
H. Schneider ◽  
J.H.M. Feyen ◽  
K. Seuwen
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Receptor ◽  
Human Parathyroid Hormone ◽  
Parathyroid Hormone Receptor

The N-Terminal Fragment of Human Parathyroid Hormone Receptor 1 Constitutes a Hormone Binding Domain and Reveals a Distinct Disulfide Pattern

Biochemistry ◽  
2000 ◽  
Vol 39 (30) ◽  
pp. 8878-8887 ◽  
Author(s):  
Ulla Grauschopf ◽  
Hauke Lilie ◽  
Konrad Honold ◽  
Manfred Wozny ◽  
Dietmar Reusch ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Receptor ◽  
Binding Domain ◽  
Human Parathyroid Hormone ◽  
Hormone Binding ◽  
Parathyroid Hormone Receptor ◽  
Terminal Fragment ◽  
Hormone Binding Domain

Binding Domain of Human Parathyroid Hormone Receptor:  From Conformation to Function†,‡

Biochemistry ◽  
1998 ◽  
Vol 37 (37) ◽  
pp. 12737-12743 ◽  
Author(s):  
Maria Pellegrini ◽  
Alessandro Bisello ◽  
Michael Rosenblatt ◽  
Michael Chorev ◽  
Dale F. Mierke
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Receptor ◽  
Binding Domain ◽  
Human Parathyroid Hormone ◽  
Parathyroid Hormone Receptor

A C-terminally truncated human parathyroid hormone receptor is functional and activates multiple G proteins

FEBS Letters ◽  
1994 ◽  
Vol 351 (2) ◽  
pp. 281-285 ◽  
Author(s):  
Helmut Schneider ◽  
Jean H.M. Feyen ◽  
Klaus Seuwen
Keyword(s):  
Parathyroid Hormone ◽  
G Proteins ◽  
Hormone Receptor ◽  
Human Parathyroid Hormone ◽  
Parathyroid Hormone Receptor

Cloning and functional expression of a human parathyroid hormone receptor

1993 ◽  
Vol 246 (2) ◽  
pp. 149-155 ◽  
Author(s):  
Helmut Schneider ◽  
Jean H.M. Feyen ◽  
Klaus Seuwen ◽  
N. Rao Movva
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Receptor ◽  
Functional Expression ◽  
Human Parathyroid Hormone ◽  
Parathyroid Hormone Receptor
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