Stereochemical Studies on Medicinal Agents. 10.¹ The Role of Chirality in α-Adrenergic Receptor Blockage by (+)- and (-)-Phenoxybenzamine Hydrochloride³

The synthesis and absolute configurational assignment of (+)- and (-)-phenoxybenzamine. HCl (1) were accomplished by utilization of (R)- and (S)-alanine as starting materials, (S)-(+)-1 was 14.5 times more potent than (S)-(-)-1 while the desmethyl analog 2 possessed intermediate αadrenergic blocking activity. Evidence is presented which suggests that the potency difference between enantiomers is due to an affinity difference for the receptor rather than to a difference in intrinsic alkylating capacity. The differences in affinity between (R)-(+ )-1, (S)-( - )-1, and 2 are postulated to be related to the abilities of the aziridinium species derived from these compounds to achieve a negative synclinal conformation and to the binding energy afforded by a properly oriented methyl group.