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.
Grunewald
Gary L
GL
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, USA. ggrunewald@ku.edu
Romero
F Anthony
FA
Criscione
Kevin R
KR
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004837:Epinephrine / Q000096:biosynthesis*; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C500062:3-fluoromethyl-7-(N-2,2,2-trifluoroethylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline; C500063:3-fluoromethyl-7-(N-3,3,3-trifluoropropylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline; D007546:Isoquinolines; D018341:Receptors, Adrenergic, alpha-2; D013449:Sulfonamides; D013450:Sulfones; D010625:Phenylethanolamine N-Methyltransferase; D004837:Epinephrine