In the search for potent and selective inhibitors of the enzyme phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28), we examined the effect of ring size or an additional heteroatom in the conformationally-restricted benzylamine-type PNMT inhibitors. Based on semiempirical calculations (MNDO) and molecular modeling studies, PNMT-inhibitory activity of these compounds seemed to be dependent on (a) the torsion angle between the plane of the aromatic ring and the endo N atom lone pair ( tau 2 angle), with the optimal value of tau 2 being about - 75 degrees, and (b) the amount of steric bulk about the 3-position of 1,2,3,4-tetrahydroisoquinoline (5, THIQ). 2,3,4,5-Tetrahydro-1H-2-benzazepine (6) was found to have the highest selectivity (PNMT Ki = 3.34 microM, alpha 2 Ki = 11 microM, selectivity = 3.2) as compared to other homologues of THIQ (PNMT Ki = 9.67 microM, alpha 2 Ki = 0.35 microM, selectivity = 0.036). The higher PNMT-inhibitory activity of 6 was attributed to favorable steric interactions of the puckered methylene groups in the putative bioactive conformation of 6 at the PNMT active site, whereas unfavorable interactions of these puckered methylene groups at the alpha 2-adrenoceptor were thought to be the cause of reduced alpha 2 affinity of 6. No further enhancement of the selectivity of the benzazepine ring system could be obtained via introduction of a second heteroatom (N, O, S) at the 5-position in this ring system.