Design and synthesis of calindol derivatives as potent and selective calcium sensing receptor agonists.

Abstract We report the first comprehensive structure–activity study of calindol ( 4 , ( R )- N -[(1 H -indol-2-yl)methyl]-1-(1-naphthyl)ethanamine), a positive allosteric modulator, or calcimimetic, of the calcium sensing receptor(CaSR). While replacement of the naphthyl moiety of calindol by other aromatic groups (phenyl, biphenyl) was largely detrimental to calcimimeticactivity, incorporation of substituents on the 4, 5 or 7 position of the indole portion of calindol was found to provide either equipotent derivatives compared to calindol (e.g., 4-phenyl, 4-hydroxy, 5-hydroxycalindol 44 , 52 , 53 ) or, in the case of 7-nitrocalindol ( 51 ), a 6-fold more active calcimimeticdisplaying an EC 50 of 20 nM. Unlike calindol, the more active CaSR calcimimeticswere shown not to act as antagonists of the closely related GPRC6Areceptor, suggesting a more selective profile for these new analogues.