Effects of a 3-alkyl-, 4-hydroxy- and/or 8-aromatic-substituent on the phenylethanolamine N-methyltransferase inhibitor potency and alpha2-adrenoceptor affinity of 2,3,4,5-tetrahydro-1H-2-benzazepines.

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 alpha2-adrenoceptor than is 1,2,3,4-tetrahydroisoquinoline (THIQ; 2) (1: PNMT K(i)= 3.3 microM, alpha2-adrenoceptor K(i) = 11 microM, selectivity [alpha2 K(i)/PNMT K(i)] = 3.3; 2: PNMT K(i) = 9.7 microM, alpha2 K(i) = 0.35 microM, 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 alpha2-adrenoceptor affinity (3: PNMT K(i) = 0.39 microM, alpha2 K(i) = 66 microM, selectivity = 170; 21: PNMT K(i) = 0.41 microM, alpha2 K(i) = 4.3 microM, selectivity = 10). Introduction of a 3-alkyl substituent on the THBA nucleus decreased both the alpha2-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 K(i) = 58 microM, alpha2 K(i) = 100 microM, selectivity = 1.7; 30: PNMT K(i) = 1.1 microM, alpha2 K(i) = 6.6 microM, 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 K(i) = 5.3 microM, alpha2 K(i) = 680 microM, selectivity = 130; 31: PNMT K(i) = 0.29 microM, alpha2 K(i) = 19 microM, selectivity = 66). Compound 3 is the most selective (PNMT/alpha2) 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).