Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarinic M1 receptors.
A set of amide- and amine-linked hybrid molecules comprising moieties of the orthosteric M(1) muscarinic receptor agonist xanomeline and the cholinesterase inhibitor and allosteric receptor modulator tacrine were prepared with varying spacer length of 10-17 atoms. The hybrids inhibited acetylcholinesterase with similar or higher potency compared to tacrine. M(1) receptor binding affinity was similar or higher relative to xanomeline and far higher relative to tacrine. Affinities hardly changed when the receptors' orthosteric site was occupied by an inverse agonist ligand. When occupied by the orthosteric activator acetylcholine, affinity for the hybrids declined to unmeasureably low levels. Hybrids did not activate M(1) receptors. In vivo studies assaying cognition impairment in rats induced by scopolamine revealed pronounced enhancement of scopolamine action. Taken together, instead of dualsteric (simultaneous allosteric/orthosteric) binding, the hybrids seem to prefer purely allosteric binding at the inactive M(1) receptor.
Center of Drug Discovery, China Pharmaceutical University, 210009 Nanjing, PR China.
Lei
L
Fang
Sabine
S
Jumpertz
Yihua
Y
Zhang
Dorothea
D
Appenroth
Christian
C
Fleck
Klaus
K
Mohr
Christian
C
Tränkle
Michael
M
Decker
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002491:Central Nervous System Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002802:Cholinesterases / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy; D005260:Female; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D018782:Maze Learning / Q000187:drug effects; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology
D002491:Central Nervous System Agents; D002800:Cholinesterase Inhibitors; D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D013830:Thiadiazoles; D013619:Tacrine; C075257:xanomeline; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases