Importance of the aromatic ring in adrenergic amines. 8. 2-(Aminomethyl)-trans-2-decalols as inhibitors of norepinephrine N-methyltransferase.

In an effort to determine the surface appearance of the hydrophobic ring binding region of the norepinephrine N-methyltransferase active site, we employed some trans-decalin analogues of 1-(aminomethyl)cycloundecanol (1), a potent NMT inhibitor. These analogues [axial and equatorial 2-(aminomethyl)-trans-2-decalol, 2 and 3] closely resemble a low energy "crown" conformation of 1. Both compounds were as potent as 1 at inhibiting NMT (Ki = 3.6, 5.6, and 3.8 microM for 1, 2, and 3, respectively), indicating that this conformation is most likely adopted within the active site in order to optimize contact with a flat hydrophobic area. None of the compounds showed significant substrate activity for NMT, a fact that is consistent with our proposed active site binding model.