Conformational Analysis of the Anti-obesity Drug Lorcaserin in Water: How To Take Advantage of Long-Range Residual Dipolar Couplings

The conformational state of 8‐chloro‐1‐methyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine hydrochloride (lorcaserin) in water has been determined on the basis of one‐bond and long‐range CH residual dipolar coupling (RDC) data along with DFT computations and 3JHH coupling‐constant analysis. According to this analysis, lorcaserin exists as a conformational equilibrium of two crown‐chair forms, of which the preferred conformation has the methyl group in an equatorial orientation. NMR‐based conformational analysis of flexible small molecules in solution is improved by the incorporation of long‐range CH residual dipolar couplings (RDCs; 2DCH) to one‐bond RDCs (1DCH; see picture). Applying this to the anti‐obesity drug, lorcaserin, shows that it exists in solution as two crown‐chair forms in equilibrium.