Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 2. 1,2,3,4-Tetrahydroisoquinoline-7-sulfonanilides.

1,2,3,4-Tetrahydroisoquinoline-7-sulfonanilides (1-14) related to 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (21,SK&F 29661) were prepared and studied for their ability to inhibit phenylethanolamine N-methyltransferase (PNMT) in vitro. The choice of substituents on the 7-phenyl group of the sulfonanilides was based on the Topliss approach to structure-activity relationship studies. Information about the importance of an acidic hydrogen atom on the sulfonamide nitrogen atom was obtained from the preparation and testing of a tertiary N-methylsulfonanilide (15). Other THIQ's (1,2,3,4-tetrahydroisoquinolines) containing sulfur substituents in the 7 position were prepared and tested and consisted of 7-N-benzyl and 7-N-phenethyl derivatives of SK&F 29661 (16-18) and 7-(phenacylthio)-and 7-(phenacylsulfonyl)-THIQ (19 and 20). The two most potent inhibitors were the 7-p-bromo- and -chlorosulfonanilides, 2 and 6. However, neither was an effective inhibitor of norepinephrine to epinephrine conversion when tested in an in vivo mouse assay at unit doses of 25 or 100 mg/kg.