Tetrahydrothiadiazoloisoquinolines: synthesis and inhibition of phenylethanolamine-N-methyltransferase

• Published in: Journal of medicinal chemistry Vol. 32; no. 7; pp. 1566 - 1571
• Main Authors: GIRARD, G. R, BONDINELL, W. E, HILLEGASS, L. M, HOLDEN, K. G, PENDLETON, R. G, UZINSKAS, I
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.07.1989
• Subjects: Adrenal Glands - enzymology; Animals; Chemical Phenomena; Chemistry; Exact sciences and technology; Heterocyclic compounds; In Vitro Techniques; Isoquinolines - chemical synthesis; Isoquinolines - pharmacology; Miscellaneous; Organic chemistry; Phenylethanolamine N-Methyltransferase - antagonists & inhibitors; Preparations and properties; Rabbits; Rats; Sulfur nitrogen heterocycle; Noradrenalin N-methyltransferase; Nitrogen heterocycle; Enzyme inhibitor; Aromatic compound; Tricyclic compound; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00127a027

A series of 7,8-fused heterocyclic tetrahydroisoquinolines were synthesized and tested as inhibitors of rabbit adrenal phenylethanolamine-N-methyltransferase (PNMT). 6,7,8,9-Tetrahydro[1,2,3]thiadiazolo[5,4-h]isoquinoline 5 (SK&F 86607) was found to be a potent inhibitor of PNMT with an IC50 similar to that of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline (1, SK&F 64139). The isomeric tetrahydro[1,2,3]thiadiazolo[4,5-h]- and tetrahydro[1,2,5]thiadiazolo[3,4-h]isoquinolines, 13 and 20, were also potent PNMT inhibitors. However, substitution of Cl at position 5 (17) resulted in loss of potency similar to the loss observed in the 5-chloro analogue of 1. The 1,2,5 isomer 20 showed only a small drop in activity at 10(-6) M. All of the thiadiazoles were more potent than the 7,8-benzo-fused analogue 36. Fusion of other five-membered heterocyclic ring systems at the 7,8-position, e.g. triazole 22 and imidazoles 24 and 26, resulted in a decrease of PNMT inhibition. The alpha-adrenoreceptor affinities of 1 and 5 were also compared.