Stereoisomer differentiation for the analgesic drug nefopam hydrochloride using modeling studies of serotonin uptake area

Equatorial and axial N‐methyl diastereomers of the analgesic drug nefopam hydrochloride were differentiated using a hypothetical model of the serotonin (5‐hydroxytryptamine) uptake area. Both diastereomers were placed within the hypothetical model area to form van der Waals interactions involving the phenyl group of nefopam, but only in the case of the equatorial N‐methyl epimer was the ⁺N—H bond able to be oriented towards the proposed hydrogen‐bonding site. A comparison of equatorial N‐methyl nefopam hydrochloride enantiomers in the proposed two‐site binding mode points to less severe nonbonding steric interactions for the (+)‐(1S,5S)‐enantiomer compared with the (−)‐(1R,5R)‐isomer.