title: Tetrahydrothiadiazoloisoquinolines: synthesis and inhibition of phenylethanolamine-N-methyltransferase.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406-0939.
authors.forename: G R
authors.initials: GR
authors.lastname: Girard
authors.forename: W E
authors.initials: WE
authors.lastname: Bondinell
authors.forename: L M
authors.initials: LM
authors.lastname: Hillegass
authors.forename: K G
authors.initials: KG
authors.lastname: Holden
authors.forename: R G
authors.initials: RG
authors.lastname: Pendleton
authors.forename: I
authors.initials: I
authors.lastname: Uzinskas
mesh_terms: D000311:Adrenal Glands / Q000201:enzymology; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats
chemical_list: D007546:Isoquinolines; D010625:Phenylethanolamine N-Methyltransferase