Tetrahydrothiadiazoloisoquinolines: synthesis and inhibition of phenylethanolamine-N-methyltransferase.
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.
Girard
G R
GR
Department of Medicinal Chemistry, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406-0939.
Bondinell
W E
WE
Hillegass
L M
LM
Holden
K G
KG
Pendleton
R G
RG
Uzinskas
I
I
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
D007546:Isoquinolines; D010625:Phenylethanolamine N-Methyltransferase