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