Probes of the Active Site of Norepinephrine N-Methyltransferase: Effect of Hydrophobic and Hydrophilic Interactions on Side-Chain Binding of Amphetamine and α-Methylbenzylamine

Article abstract of DOI:10.1021/jm00352a031

A series of ω-substituted analogues of amphetamine and α-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 theterminal methyl group of the lead compounds is situated close to a hydrophilic area or hydrogen bonding functional group within the active site.