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

Grunewald, Gary L., Seim, Mitchell R., Regier, Rachel C., Martin, Jennifer L., Gee, Christine L., Drinkwater, Nyssa and Criscione, Kevin 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. doi:10.1021/jm060466d


Author Grunewald, Gary L.
Seim, Mitchell R.
Regier, Rachel C.
Martin, Jennifer L.
Gee, Christine L.
Drinkwater, Nyssa
Criscione, Kevin R.
Title 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 name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2006
Sub-type Article (original research)
DOI 10.1021/jm060466d
Volume 49
Issue 18
Start page 5424
End page 5433
Total pages 10
Editor Philip S. Portoghese
Place of publication Washington, DC, USA
Publisher American Chemical Society
Collection year 2006
Language eng
Subject C1
250302 Biological and Medical Chemistry
730104 Nervous system and disorders
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 R2-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 K-i = 1.3 mu M) is the most potent compound in this series and is quite selective for PNMT versus the R2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT K-i = 0.13 mu M). 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.
Keyword Chemistry, Medicinal
Display Remarkable Potency
Blood-brain-barrier
Selective Inhibitors
Biochemical Evaluation
Alzheimers-disease
F 29661
Alpha(2)-adrenoceptor
Protein
Pnmt
Sk
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 08:32:51 EST