Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[ h]isoquinoline inhibitors

• Published in: Bioorganic & medicinal chemistry 2007-02, Vol.15 (3), p.1298-1310
• Main Authors: Grunewald, Gary L., Seim, Mitchell R., Regier, Rachel C., Criscione, Kevin R.
• Format: Article
• Language: English
• Subjects: 1,2,3,4-Tetrahydrobenz[ h]isoquinoline; Analytical, structural and metabolic biochemistry; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Enzyme inhibitors; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Phenylethanolamine N-methyltransferase; Phenylethanolamine N-Methyltransferase - antagonists & inhibitors; Radioligand Assay; Receptors, Adrenergic, alpha-2 - metabolism; Structure-Activity Relationship; Structure-based design; Tetrahydroisoquinolines - pharmacology; Transferases
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.11.010

A series of 7-substituted-1,2,3,4-tetrahydrobenz[ h]isoquinolines were synthesized and examined as potential inhibitors of phenylethanolamine N-methyltransferase (PNMT), the enzyme responsible for the conversion of norepinephrine to epinephrine. 1,2,3,4-Tetrahydrobenz[ h]isoquinoline (THBQ, 11) is a potent, inhibitor of phenylethanolamine N-methyltransferase (PNMT). Docking studies indicated that the enhanced PNMT inhibitory potency of 11 (hPNMT K i = 0.49 μM) versus 1,2,3,4-tetrahydroisoquinoline ( 5, hPNMT K i = 5.8 μM) was likely due to hydrophobic interactions with Val53, Met258, Val272, and Val269 in the PNMT active site. These studies also suggested that the addition of substituents to the 7-position of 11 that are capable of forming hydrogen bonds to the enzyme could lead to compounds ( 14– 18) having enhanced PNMT inhibitory potency. However, these compounds are in fact less potent at PNMT than 11. Furthermore, 7-bromo-THBQ ( 19, hPNMT K i = 0.22 mM), which has a lipophilic 7-substituent that cannot hydrogen bond to the enzyme, is twice as potent at PNMT than 11. This once again illustrates the limitations of docking studies for lead optimization.