Importance of the aromatic ring in adrenergic amines. 7. Comparison of the stereoselectivity of norepinephrine N-methyltransferase for aromatics. Nonaromatic substrates and inhibitors

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Abstract
Some nonaromatic analogs of amphetamine and .alpha.-methylbenzylamine were prepared and evaluated as competitive inhibitors of norepinephrine N-methyltransferase (NMT). All of the nonaromatic analogs were significantly more active than their aromatic counterparts [Ki for amphetamine = 740 .mu.M; Ki for 1-cyclooctyl-2-aminopropane = 86 .mu.M]. To determine if the aliphatic ring of these analogs 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 analogs was also found to be the same; as the lipophilicity of the nonaromatic ethanolamine analogs was increased, a loss in both stereoselectivity and substrate activity occurred. These results 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.

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