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Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4- tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase

Journal Article


Abstract


  • 3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4- tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4- tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH- could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH- with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the α2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT Ki = 1.3 μM) is the most potent compound in this series and is quite selective for PNMT versus the α2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT Ki = 0.13 μM). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones. © 2006 American Chemical Society.

UOW Authors


  •   Grunewald, Gary (external author)
  •   Seim, Mitchell (external author)
  •   Regier, Rachel (external author)
  •   Martin, Jennifer
  •   Gee, Christine (external author)
  •   Drinkwater, Nyssa (external author)
  •   Criscione, Kevin (external author)

Publication Date


  • 2006

Citation


  • Grunewald, G. L., Seim, M. R., Regier, R. C., Martin, J. L., Gee, C. L., Drinkwater, N. & Criscione, K. R. (2006). Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4- tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase. Journal of Medicinal Chemistry, 49 (18), 5424-5433.

Scopus Eid


  • 2-s2.0-33748550689

Number Of Pages


  • 9

Start Page


  • 5424

End Page


  • 5433

Volume


  • 49

Issue


  • 18

Place Of Publication


  • United States

Abstract


  • 3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4- tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4- tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH- could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH- with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the α2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT Ki = 1.3 μM) is the most potent compound in this series and is quite selective for PNMT versus the α2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT Ki = 0.13 μM). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones. © 2006 American Chemical Society.

UOW Authors


  •   Grunewald, Gary (external author)
  •   Seim, Mitchell (external author)
  •   Regier, Rachel (external author)
  •   Martin, Jennifer
  •   Gee, Christine (external author)
  •   Drinkwater, Nyssa (external author)
  •   Criscione, Kevin (external author)

Publication Date


  • 2006

Citation


  • Grunewald, G. L., Seim, M. R., Regier, R. C., Martin, J. L., Gee, C. L., Drinkwater, N. & Criscione, K. R. (2006). Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4- tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase. Journal of Medicinal Chemistry, 49 (18), 5424-5433.

Scopus Eid


  • 2-s2.0-33748550689

Number Of Pages


  • 9

Start Page


  • 5424

End Page


  • 5433

Volume


  • 49

Issue


  • 18

Place Of Publication


  • United States