To probe the importance of pi-electronic and steric interactions of nonaromatic analogues of phenylethanolamine as inhibitors of phenylethanolamine N-methyltransferase (PNMT), a series of norbornane and norbornene ethanolamines was prepared and evaluated as inhibitors of PNMT (liquid chromatographic-electrochemical detector assay). Previous studies indicated a major importance of hydrophobic interaction of the ring moiety attached to the ethanolamine side chain, but a possible importance of pi-complex formation could have been obscured by conformational differences among the analogues. In this study, norbornane and norbornene substituted with an ethanolamine side chain at positions 1,2-exo, and 2-endo were prepared from the corresponding aldehydes by addition of trimethylsilyl cyanide (Me3SiCN) and lithium aluminum hydride reduction. The saturated (norbornane) analogues were two times more potent as inhibitors of the enzyme than were the norbornene analogues, thus suggesting that pi-complex formation is not an important contribution to binding and, as previously proposed, a hydrophobic interaction is the significant binding interaction of the ring moiety. The hydrophobic binding area has a critical size that requires the hydrophobic moiety to be of sufficient length (the bridgehead-substituted norbornane and norbornene ethanolamines being too "'short" for optimal binding). The 2-exo orientation of the ethanolamine side chain was preferred to the 2-endo orientation, supporting our earlier hypothesis that the ring moiety prefers to be oriented away from the side chain.