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.

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.