N2-benzyl-N1-(1-(1-naphthyl)ethyl)-3-phenylpropane-1,2-diamines and conformationally restrained indole analogues: development of calindol as a new calcimimetic acting at the calcium sensing receptor.
The synthesis and calcimimetic activities of two new families of compounds are described. The most active derivatives of the first family, N(2)-(2-chloro-(or 4-fluoro-)benzyl)-N(1)-(1-(1-naphthyl)ethyl)-3-phenylpropane-1,2-diamine (4b and 4d, respectively, tested at 10 microM) produced 98+/-6% and 95+/-4%, respectively, of the maximal stimulation of [(3)H]inositol phosphates production obtained by 10mM Ca(2+) in CHO cells expressing the rat calcium sensing receptor (CaSR). The second family of calcimimetics was obtained by conformationally restraining the compounds of type 4 to provide the 2-aminomethyl derivatives 5. One of these compounds, (R)-2-[N-(1-(1-naphthyl)ethyl)aminomethyl]indole ((R)-5a, calindol), displayed improved calcimimetic activity compared to 4b and 4d as well as stereoselectivity. In the presence of 2mM Ca(2+), calindol stimulated [(3)H]inositol phosphates accumulation with an EC(50) of 1.0+/-0.1 or 0.31+/-0.05 microM in cells expressing the rat or the human CaSR, respectively. The calcimimetic activities of these novel compounds were shown to be due to a specific interaction with the CaSR.
Kessler
Albane
A
Institut de Chimie des Substances Naturelles, UPR 2301 Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvette Cedex, France.
Faure
Hélène
H
Petrel
Christophe
C
Ruat
Martial
M
Dauban
Philippe
P
Dodd
Robert H
RH
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D006224:Cricetinae; D003959:Diamines / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008968:Molecular Conformation; D018716:Molecular Mimicry; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*
D003959:Diamines; D007211:Indoles; D008024:Ligands; D044169:Receptors, Calcium-Sensing; D002118:Calcium