Nanomolar inhibitors of CNS epinephrine biosynthesis: (R)-(+)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines as potent and highly selective inhibitors of phenylethanolamine N-methyltransferase1.

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Grunewald GL, Romero FA, Criscione KR

J Med Chem. 2005 Mar 24;48(6):1806-12.

PubMed ID

15771426 [ View in PubMed

]

Abstract

A series of (R)-(+)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines has been synthesized and evaluated as inhibitors of PNMT and for their affinity for the alpha(2)-adrenoceptor. Compounds (R)-8 and (R)-9 are remarkably potent and selective inhibitors of PNMT and are predicted to penetrate the blood-brain barrier on the basis of their calculated log P values. Conformational analysis and docking studies were performed in order to examine why the (R)-enantiomer of these 3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines is more potent than the (S)-enantiomer and to determine the likely bound ring conformer of the (R)-enantiomer. It appears that the (R)-enantiomer participates in a water-mediated hydrogen bond in which the (S)-enantiomer cannot. The likely favored ring conformation for (R)-3-fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines in the PNMT active site is similar to the ring conformation of (R)-5a as determined by gas-phase ab initio calculations.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(3R)-3-(FLUOROMETHYL)-7-(THIOMORPHOLIN-4-YLSULFONYL)-1,2,3,4-TETRAHYDROISOQUINOLINE	Phenylethanolamine N-methyltransferase	Ki (nM)	610	N/A	N/A	Details
(3R)-3-(FLUOROMETHYL)-N-(3,3,3-TRIFLUOROPROPYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE	Phenylethanolamine N-methyltransferase	Ki (nM)	99	N/A	N/A	Details