NMR-STUDIES OF DRUGS - APPLICATIONS OF ACHIRAL AND CHIRAL LANTHANIDE SHIFT-REAGENTS TO MEDETOMIDINE - OBSERVATIONS OF ANOMALOUS SHIFTS.

The 60 MHz H-1 NMR spectra of the potent, selective and specific alpha(2)-adrenoceptor agonist, medetomidine, have been studied in CDCl3 at 28+/-1 degrees for the racemic free base, 1, with the added achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedianato)europium(III), 2 for spectral simplification, and with the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), 3, and tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato]europium(III), 4, for potential enantiomeric shift differences. Substantial lanthanide-induced shifts (LIS) were observed with each added LSR, consistent with LSR binding at the basic imidazole nitrogen. The three LSRs gave distinctly different LIS results for the NH signal, with substantial ''anomalous'' (upfield) shifts observed with 2 and smaller anomalous shifts produced with 3, at low [LSR]:[1] ratios; normal downfield shifts resulted at higher LSR levels of 2 or 3. With LSR 4, only consistent ''normal'' downfield shifts were seen for the NH signal.