In order to determine the active site binding orientation of norepinephrine, a series of conformationally defined analogues of the tyramines, in which the ethylamine side chain is held fixed by incorporation into a benzonorbornene skeleton, were prepared and evaluated for phenylethanolamine N-methyltransferase (PNMT) activity. While exo-2-amino-5- and exo-2-amino-8-hydroxybenzonorbornene (7 and 10, respectively) were prepared from 5-methoxybenzonorbornadiene by azidomercuration/demercuration and reduction, it was necessary to employ both normal (inversion of configuration) and abnormal (retention of configuration) Mitsunobu reactions to prepare, stereoselectively, exo-2-amino-6- and exo-2-amino-7-hydroxybenzonorbornene (8 and 9, respectively) from 6- and 7-methoxybenzonorbornen-2-ol. None of the six analogues were substrates. However, exo-2-amino-6-hydroxybenzonorbornene (8) and anti-9-amino-6-hydroxybenzonorbornene (12) displayed significant activity as inhibitors toward PNMT. The greater potency of 8 and 12, as compared to the parent unsubstituted analogues exo-2-amino- and anti-9-amino-benzonorbornene (4 and 5, respectively), indicates the presence of a spatially compact hydrophilic pocket within the aromatic ring binding region of the active site of the enzyme. Furthermore, the greater activity of 12, relative to 8, is consistent with an active site binding preference for molecules in which a more coplanar relationship exists between the aromatic ring and the amine nitrogen. From the findings of this study, it appears that norepinephrine has a different active site binding orientation than most known substrates and competitive inhibitors of PNMT.