title: Hyperbolic mixed-type inhibition of acetylcholinesterase by tetracyclic thienopyrimidines.
abstract: A series of tetracyclic thienopyrimidines (7-14) was prepared and investigated as inhibitors of acetylcholinesterase from Electrophorus electricus acetylcholinesterase (EeAChE), as well as human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). A new synthetic procedure was employed for the synthesis of the angularly fused heterocycles 7-10. Among them, the presence of a tetrahydropyrido ring with a benzyl rest at the basic nitrogen was required for EeAChE inhibition. A detailed kinetic analysis of the hyperbolic mixed-type inhibition of EeAChE by 9-14 was performed. These heterocyclic compounds inhibited EeAChE with K(i) values of less than 3 µM. Most α values were relatively close to 1, indicating a similar affinity of the inhibitor to the free enzyme and the enzyme-substrate complex. Inhibitor 10 displayed a rather uncompetitive pattern of inhibition (α = 0.47) and a relatively high residual activity of a postulated ternary enzyme-substrate-inhibitor complex (β = 0.24).
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
authors.forename: C M González
authors.initials: CM
authors.lastname: Tanarro
authors.forename: M
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004593:Electrophorus; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D000110:Acetylcholinesterase