Some nonaromatic analogues of amphetamine and alpha-methylbenzylamine were prepared and evaluated as competitive inhibitors of norepinephrine N-methyltransferase (NMT). All of the nonaromatic analogues were significantly more active than their aromatic counterparts [Ki for amphetamine = 740 microM; Ki for 1-cyclooctyl-2-aminopropane = 86 microM]. In order to determine if the aliphatic ring of these analogues bound to the same binding site as the phenyl ring of amphetamine and alpha-methylbenzylamine, the stereoselectivity of NMT toward the different compounds was determined. Stereochemical requirements for aromatic and nonaromatic inhibitors were similar (in all cases the S isomer was more potent at inhibiting NMT). The stereochemical preference expressed for phenylethanolamine substrates and corresponding nonaromatic analogues was also found to be the same; however, as the lipophilicity of the nonaromatic ethanolamine analogues was increased, a loss in both stereoselectivity and substrate activity occurred. The results presented here are consistent with an aromatic ring binding site that is part of, or bordered by, a large hydrophobic area. The larger, more hydrophobic nonaromatic phenylethanolamine derivatives are drawn into the hydrophobic area, which reduces side-chain hydroxy interactions necessary for substrate activity.