Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 3. Bis[tetrahydroisoquinoline]s.

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DeMarinis RM, Bryan WM, Hillegass LM, McDermott D, Pendleton RG

Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 3. Bis[tetrahydroisoquinoline]s.

J Med Chem. 1981 Jun;24(6):756-9.

PubMed ID

7252985 [ View in PubMed

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Abstract

7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (SK&F 64139) is a potent inhibitor of phenylethanolamine N-methyltransferase (IC50 = 10 muM) that may have therapeutic utility in man. A series of related compounds in which two 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline molecules have been bridged from nitrogen to nitrogen by an unbranched alkyl chain have been prepared and have demonstrated potent inhibitory properties (0.08 to 2 muM). In contrast simple substitution on the nitrogen of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline with a variety of substituents gives compounds with greatly diminished inhibitory potencies (IC50 = 2 to greater than 100 muM) relative to SK&F 64139. Kinetic studies with a C6 analogue have shown that it is competitive with respect to phenylethanolamine and uncompetitive with respect to S-adenosylmethionine. The increased potency of some of the bis analogues relative to that seen with the tetrahydroisoquinolines having larger alkyl groups on nitrogen suggests that several of the bis compounds show supplemented or cooperative binding to the enzyme, presumably as a result of the second tetrahydroisoquinoline moiety.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline	Phenylethanolamine N-methyltransferase	IC 50 (nM)	10	N/A	N/A	Details
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline	Phenylethanolamine N-methyltransferase	IC 50 (nM)	10000	N/A	N/A	Details