52516-30-0Relevant articles and documents
Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor
Setola, Vincent,Dukat, Malgorzata,Glennon, Richard A.,Roth, Bryan L.
, p. 20 - 33 (2005)
S-(+)-Norfenfluramine (SNF)-an active metabolite of the now-banned anorexigen fenfluramine-has been implicated in the drug's appetite-suppressing actions and its life-threatening cardiovascular side effects. SNF reduces appetite through serotonin 5-HT2C receptor activation; it causes cardiopulmonary side effects through 5-HT2B receptor activation. Thus, we attempted to identify molecular determinants of SNF binding to 5-HT2B receptors distinct from those underlying SNF-5-HT 2C/2A receptor interactions. Mutagenesis implicated Val2.53 in SNF binding to 5-HT2B receptors. Ligand docking simulations suggested both Val2.53 γ-methyl groups form stabilizing van der Waals' (vdW) interactions with the α-methyl group of SNF. A V2.53L mutation induced a 17-fold decrease in affinity; molecular dynamics (MD) simulations suggested that this decrease resulted from the loss of one 2.53-α-methyl group vdW interaction. Supporting this, 1) the binding of norfenfluramine (NF) analogs lacking an S-(+) α-methyl group (RNF and α-desmethyl-NF) was less sensitive to the V2.53L mutation, and 2) a V2.53A mutation decreased SNF affinity 190-fold, but decreased RNF and α-desmethyl-NF affinities only 16- and 45-fold, respectively. We next addressed whether the α-methyl group of SNF contributes to 5-HT2C/2A receptor affinity. Removal of the α-methyl group (RNF and α-desmethyl-NF), which reduced 5-HT 2B receptor binding 3-fold, did not affect 5-HT2C/2A receptor binding. An α-ethyl substituent (α-ethyl-NF), which decreased 5-HT2B receptor affinity 46-fold, reduced 5-HT2C and 5-HT2A receptor binding by 14- and 5-fold, respectively. Finally, we determined that residue 2.53 affects SNF potency and efficacy at 5-HT2B receptors but not at 5-HT2C and 5-HT2A receptors. In conclusion, vdW interactions between residue 2.53 and the α-methyl group of SNF contribute to the ligand's 5-HT2 receptor subtype-selective pharmacology. Copyright
17a-HYDROXYLASE/C17,20-LYASE INHIBITORS
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Paragraph 0416, (2014/03/21)
The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R6, A and n are as defined herein. A deuteriated derivative of the compound of Formula (I) is also provided.
Regioselective hydroboration-oxidation and -amination of fluoro-substituted styrenes
Ramachandran, P. Veeraraghavan,Madhi, Sateesh,O'Donnell, Martin J.
, p. 1252 - 1255 (2008/09/20)
Hydroboration of fluorinated styrenes with common hydroborating agents results in polymerization. However, regioselective hydroboration has been achieved by utilizing iodoborane-dimethyl sulfide. A series of fluorinated β-phenethyl alcohols and amines were synthesized via this methodology.
