Effects of a 3-alkyl-, 4-hydroxy- and/or 8-aromatic-substituent on the phenylethanolamine N-methyltransferase inhibitor potency and alpha(2)-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 selec tive an inhibitor of phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1 .28) versus the alpha (2)-adrenoceptor than is 1,2,3,4-tetrahydroisoquinoli ne (THIQ; 2) (1: PNMT K-i = 3.3 muM, alpha (2)-adrenoceptor K-i = 11 muM, s electivity [alpha (2) K-i/PNMT K-i = 3.3; 2: PNMT K-i = 9.7 muM, alpha (2) K-i = 0.35 muM, selectivity 0.036;). Since the PNMT inhibitory activity and selectivity of THIQ were enhanced by the introduction of a hydrophilic ele ctron-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 inhibi tor of PNMT as its THIQ analogue (21) and to be more selective due to its r educed alpha (2)-adrenoceptor affinity (3: PNMT K-i = 0.39 muM, alpha (2) K -i = 66 muM, selectivity = 170; 21: PNMT K-i = 0.41 muM, (alpha (2) K-i = 4 .3 muM, selectivity = 10). Introduction of a 3-alkyl substituent on the THB A nucleus decreased both the alpha (2)-adrenoceptor affinity and the PNMT i nhibitory activity, suggesting an area of steric bulk intolerance at both s ites. 4-Hydroxy-THBA (15), which can be considered a conformationally-restr icted analogue of 3-hydroxymethyl-THIQ (30), exhibited poorer PNMT inhibito ry activity and less selectivity than 30 (15: PNMT K-i = 58 muM, alpha (2) K-i = 100 muM, selectivity = 1.7; 30 PNMT K-i = 1.1 muM, alpha (2) K-i = 6. 6 muM, selectivity = 6.0). While the addition of an 8-nitro group to 15 inc reased 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 muM, alpha (2) K-i = 680 muM, selectivity = 130; 31: PNMT K-i = 0.29 mu M, alpha (2) K-i = 19 muM, selectivity = 66). Compound 3 is the most select ive (PNMT/alpha (2) and one of the more potent at PNMT compounds yet report ed in the benzazepine series, and should have sufficient lipophilicity to p enetrate the blood-brain barrier (CLogP = 1.8). (C) 2001 Elsevier Science L td. All rights reserved.