title: 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-[(1H-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 calcimimetic activity, 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 calcimimetic displaying an EC50 of 20nM. Unlike calindol, the more active CaSR calcimimetics were shown not to act as antagonists of the closely related GPRC6A receptor, suggesting a more selective profile for these new analogues.
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR-2301, CNRS, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Kiefer
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR-2301, CNRS, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Beaumard
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay, Signal Transduction and Developmental Neuropharmacology Team, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gorojankina
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay, Signal Transduction and Developmental Neuropharmacology Team, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Faure
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay, Signal Transduction and Developmental Neuropharmacology Team, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France.
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR-2301, CNRS, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France. Electronic address: robert.dodd@cnrs.fr.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Dodd
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044169:Receptors, Calcium-Sensing / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C506457:(R)-2-(1-(1-naphthyl)ethyl-aminom-ethyl)indole; D007211:Indoles; D009281:Naphthalenes; D044169:Receptors, Calcium-Sensing
keywords: Calcimimetic; Calcium sensing receptor; Calindol; Hyperparathyroidism; Indole; Parathyroid hormone