Effects of a 3-Alkyl-, 4-Hydroxy- and/or 8-Aromatic-substituent on the Phenylethanolamine N-Methyltransferase Inhibitor Potency and α2-Adrenoceptor Affinity of 2,3,4,5-Tetrahydro-1H-2-benzazepines Original Research Article

2,3,4,5-Tetrahydro-1H-2-benzazepine (THBA; 1) is nearly 100-fold more selective an inhibitor of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) versus the α2-adrenoceptor than is 1,2,3,4-tetrahydroisoquinoline (THIQ; 2) (1: PNMT Ki=3.3 μM, α2-adrenoceptor Ki=11 μM, selectivity [α2 Ki/PNMT Ki]=3.3; 2: PNMT Ki=9.7 μM, α2 Ki=0.35 μM, selectivity=0.036;). Since the PNMT inhibitory activity and selectivity of THIQ were enhanced by the introduction of a hydrophilic electron-withdrawing 7-substituent and a 3-alkyl-substituent, a similar study was conducted on THBA. 8-Nitro-THBA (3) was found to be as potent an inhibitor of PNMT as its THIQ analogue (21) and to be more selective due to its reduced α2-adrenoceptor affinity (3: PNMT Ki=0.39 μM, α2 Ki=66 μM, selectivity=170; 21: PNMT Ki=0.41 μM, α2 Ki=4.3 μM, selectivity=10). Introduction of a 3-alkyl substituent on the THBA nucleus decreased both the α2-adrenoceptor affinity and the PNMT inhibitory activity, suggesting an area of steric bulk intolerance at both sites. 4-Hydroxy-THBA (15), which can be considered a conformationally-restricted analogue of 3-hydroxymethyl-THIQ (30), exhibited poorer PNMT inhibitory activity and less selectivity than 30 (15: PNMT Ki=58 μM, α2 Ki=100 μM, selectivity=1.7; 30: PNMT Ki=1.1 μM, α2 Ki=6.6 μM, selectivity=6.0). While the addition of an 8-nitro group to 15 increased the selectivity of 16 as compared to its THIQ analogue (31), it was not as potent at PNMT nor as selective as 8-nitro-THBA (3) (16, PNMT Ki=5.3 μM, α2 Ki=680 μM, selectivity=130; 31: PNMT Ki=0.29 μM, α2 Ki=19 μM, selectivity=66). Compound 3 is the most selective (PNMT/α2) and one of the more potent at PNMT compounds yet reported in the benzazepine series, and should have sufficient lipophilicity to penetrate the blood–brain barrier (CLogP=1.8).