5'-thioadenosine derivatives as potent and selective inhibitors of histamine N-methyltransferase.
Several new analogues of adenosine bearing a lipophilic side chain at the 5'-position have been synthesized and investigated for their ability to inhibit histamine N-methyltransferase (HNMT). The 5'-deoxy-5'-[4-(3-indolyl)but-1-yl]thio]adenosine (2e), exhibited a pI50 of 5.00 against guinea pig brain HNMT. Interestingly, the polar methyl sulphonium analogue (1c) was a more potent inhibitor of this enzyme (pI50 = 5.26). Both compounds were relatively ineffective inhibitors of rabbit adrenal phenylethanolamine N-methyltransferase (PNMT), rabbit lung indoleamine N-methyltransferase (INMT), and rat brain catechol O-methyltransferase (COMT). 5'-[N(4-phenylbutyl)]-amino-5'deoxyadenosine (2a) and 5'-[N-methyl,N-(4-phenylbutyl]-amino-5'deoxyadenosine (2b) also exhibited potent and selective inhibition against guinea pig brain HNMT. Results from kinetic studies indicate that the above compounds are inhibitors that compete for both the histamine and the S-adenosylmethionine (SAM) binding sites of HNMT. Compound 1c is one of the most potent adenosine analogue inhibitors of HNMT known.
Crooks
P A
PA
College of Pharmacy, University of Kentucky, Lexington 40536.
Hassan
S F
SF
Benghiat
E
E
Hemrick-Luecke
S K
SK
Fuller
R W
RW
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000311:Adrenal Glands / Q000201:enzymology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007700:Kinetics; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors; D011817:Rabbits; D051381:Rats; D012436:S-Adenosylmethionine / Q000378:metabolism; D013872:Thionucleosides / Q000138:chemical synthesis / Q000494:pharmacology*
D013872:Thionucleosides; C063476:5'-thioadenosine; D012436:S-Adenosylmethionine; D008780:Methyltransferases; D010625:Phenylethanolamine N-Methyltransferase; D006637:Histamine N-Methyltransferase; D000241:Adenosine