Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 1. Chloro-substituted 1,2,3,4-tetrahydroisoquinolines.

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Bondinell WE, Chapin FW, Girard GR, Kaiser C, Krog AJ, Pavloff AM, Schwartz MS, Silvestri JS, Vaidya PD, Lam BL, Wellman GR, Pendleton RG

Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 1. Chloro-substituted 1,2,3,4-tetrahydroisoquinolines.

J Med Chem. 1980 May;23(5):506-11.

PubMed ID

7381849 [ View in PubMed

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Abstract

In a search for inhibitors of epinephrine biosynthesis as potential therapeutic agents, a series of 13 ring-chlorinated 1,2,3,4-tetrahydroisoquinolines was prepared. These compounds were tested initially for their ability to inhibit rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) in vitro. Enzyme-inhibitor dissociation constants, determined for the six most potent members of the series, indicated the following order of decreasing potency: 7,8-Cl2 greater than 6,7,8-Cl3 greater than 7-Cl approximately 5,6,7,8-Cl4 greater than 5,7,8-Cl3. These compounds were subsequently examined for PNMT-inhibiting activity in intact rats and mice. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (13, SK&F 64139) was the most potent member of the series both in vitro and in vivo and is currently undergoing clinical investigation.

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	Ki (nM)	3	N/A	N/A	Details