Probes of the active site of norepinephrine N-methyltransferase: effect of hydrophobic and hydrophilic interactions on side-chain binding of amphetamine and alpha-methylbenzylamine.

A series of omega-substituted analogues of amphetamine and alpha-methylbenzylamine were prepared and evaluated as inhibitors of norepinephrine N-methyltransferase (NMT). These included several alkyl side chain extended analogues (1-5), as well as the terminally hydroxylated derivatives phenylalanol (6a) and phenylglycinol (7a). None of the alkyl-substituted derivatives displayed appreciable activity as inhibitors; however, the hydroxylated analogues were up to twofold more potent than the parent compounds. The positive contribution of the side-chain hydroxy suggests that the terminal methyl group of the lead compounds is situated close to a hydrophilic area or hydrogen bonding functional group within the active site.