title: 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.
abstract: 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).
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence 66045, USA. ggrunewald@ukans.edu
authors.forename: G L
authors.initials: GL
authors.lastname: Grunewald
authors.forename: V H
authors.initials: VH
authors.lastname: Dahanukar
authors.forename: K R
authors.initials: KR
authors.lastname: Criscione
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011564:Furocoumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D009498:Neurotoxins / Q000494:pharmacology; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D044005:Tetrahydroisoquinolines
chemical_list: D004791:Enzyme Inhibitors; D011564:Furocoumarins; D007546:Isoquinolines; D009498:Neurotoxins; D018341:Receptors, Adrenergic, alpha-2; D044005:Tetrahydroisoquinolines; C059470:tetrahydrobenzo-4,6-dimethylangelicin; C014843:1,2,3,4-tetrahydroisoquinoline; D010625:Phenylethanolamine N-Methyltransferase