Synthesis and anticholinesterase activity of (-)-N1-norphysostigmine, (-)-eseramine, and other N(1)-substituted analogues of (-)-physostigmine.
(-)-N1-Benzylnorphysostigmine (4), prepared from synthetic (-)-O-methyl-N1-noreseroline (1) by N-benzylation, ether cleavage, and reaction of (-)-N1-benzylnoreseroline (3) with methyl isocyanate, was the intermediate used to prepare the title compounds. Catalytic debenzylation of 4 afforded (-)-N1-norphysostigmine (5), and (-)-eseramine (6) was obtained by reaction of 5 with methyl isocyanate. Reductive N-methylation of 5 gave (-)-physostigmine (9) while reaction of 5 with allyl bromide and phenethyl bromide afforded carbamates 7 and 8, respectively. Data on the in vitro potencies (IC50) and activities of certain of these compounds (4-8) as inhibitors of electric eel acetyl cholinesterase are reported. (-)-N1-Norphysostigmine (5) was found to be similarly potent against AChE as (-)-physostigmine (9).
Yu
Q S
QS
Medicinal Chemistry Section, NIDDK, Bethesda, Maryland 20892.
Atack
J R
JR
Rapoport
S I
SI
Brossi
A
A
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004593:Electrophorus; D008745:Methylation; D010830:Physostigmine / Q000031:analogs & derivatives*
D002800:Cholinesterase Inhibitors; D010830:Physostigmine