EFFECT OF RING SIZE OR AN ADDITIONAL HETEROATOM ON THE POTENCY AND SELECTIVITY OF BICYCLIC BENZYLAMINE-TYPE INHIBITORS OF PHENYLETHANOLAMINE N-METHYLTRANSFERASE

In the search for potent and selective inhibitors of the enzyme phenyl ethanolamine N-ethyltransferase (PNMT; EC 2.1.1.28), we examined the e ffect of ring size or an additional hetero atom in the conformationall y-restricted benzylamine-type PNMT inhibitors. Based on semiempirical calculations (MNDO) and molecular modeling studies, PNMT-inhibitory ac tivity of these compounds seemed to be dependent on (a) the torsion an gle between the plane of the aromatic ring and the endo N atom lone pa ir (tau(2) angle), with the optimal value of tau(2) being about -75 de grees, and (b) the amount of steric bulk ab out the 3-position of 1,2, 3,4-tetrahydroisoquinoline (5, THIQ). 2,3,4,5-Tetrahydro-1H-2-benzazep ine (6) was found to have the highest selectivity (PNMT K-i = 3.34 mu M, alpha(2) K-i = 11 mu M, selectivity = 3.2) as compared to other hom ologues of THIQ (PNMT K-i = 9.67 mu M, alpha(2) K-i = 0.35 mu M, selec tivity = 0.036). The higher PNMT-inhibitory activity of 6 was attribut ed to favorable steric interactions of the puckered methylene groups i n the putative bioactive conformation of 6 at the PNMT active site, wh ereas unfavorable interactions of these puckered methylene groups at t he alpha(2)-adrenoceptor were thought to be the cause of reduced alpha (2) affinity of 6. No further enhancement of the selectivity of the be nzazepine ring system could be obtained via introduction of a second h eteroatom (N, O, S) at the 5-position in this ring system.