Structural features of potent inhibitors of rat kidney histamine N-methyltransferase.
Three antimalarial drugs amodiaquine, quinacrine and chloroquine were compared side-by-side with the antiseptic agent chlorhexidine and the neuromuscular blocker alcuronium for their capacity to competitively inhibit in vitro the activity of the enzyme histamine N-methyltransferase (HMT) from rat kidney over the concentration range 10(-3)-10(-8). Amodiaquine was clearly the most potent HMT inhibitor followed by quinacrine, chlorhexidine, alcuronium and chloroquine. Investigation of the structure-activity relationships by examining space-filling models revealed marked similarities in the conformations of the arrangement of three N atoms in histamine and in each of the compounds tested.
Harle
D G
DG
Kolling Institute of Medical Research, Royal North Shore Hospital of Sydney, St. Leonards, N.S.W. Australia.
Baldo
B A
BA
D000443:Alcuronium / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D001667:Binding, Competitive; D002710:Chlorhexidine / Q000494:pharmacology; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000962:Antimalarials; D008780:Methyltransferases; D006637:Histamine N-Methyltransferase; D002710:Chlorhexidine; D000443:Alcuronium