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

J Med Chem. 2005 Mar 24;48(6):1806-12. doi: 10.1021/jm049594x.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Brain / metabolism*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Epinephrine / biosynthesis*
  • Hydrogen Bonding
  • In Vitro Techniques
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Phenylethanolamine N-Methyltransferase / antagonists & inhibitors*
  • Phenylethanolamine N-Methyltransferase / chemistry*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-2 / drug effects
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology

Substances

  • 3-fluoromethyl-7-(N-2,2,2-trifluoroethylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline
  • 3-fluoromethyl-7-(N-3,3,3-trifluoropropylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline
  • Isoquinolines
  • Receptors, Adrenergic, alpha-2
  • Sulfonamides
  • Sulfones
  • Phenylethanolamine N-Methyltransferase
  • Epinephrine