Jordis U

References (2)

Title : Memogain is a galantamine pro-drug having dramatically reduced adverse effects and enhanced efficacy - Maelicke_2010_J.Mol.Neurosci_40_135
Author(s) : Maelicke A , Hoeffle-Maas A , Ludwig J , Maus A , Samochocki M , Jordis U , Koepke AK
Ref : Journal of Molecular Neuroscience , 40 :135 , 2010
Abstract : Memogain (Gln-1062) is an inactive pro-drug of galantamine, the latter being a plant alkaloid approved for the treatment of mild to moderate Alzheimer's disease. Memogain has more than 15-fold higher bioavailability in the brain than the same doses of galantamine. In the brain, Memogain is enzymatically cleaved to galantamine, thereby regaining its pharmacological activity as a cholinergic enhancer. In animal models of drug-induced amnesia, Memogain produced several fold larger cognitive improvement than the same doses of galantamine, without exhibiting any significant levels of gastrointestinal side effects that are typical for the unmodified drug and other inhibitors of cholinesterases, such as donepezil and rivastigmin. In the ferret, dramatically reduced emetic and behavioral responses were observed when Memogain was administered instead of galantamine. Based on these and other preclinical data, Memogain may represent an advantageous drug treatment for Alzheimer's disease, combining much lesser gastrointestinal side effects and considerably higher potency in enhancing cognition, as compared to presently available drugs.
ESTHER : Maelicke_2010_J.Mol.Neurosci_40_135
PubMedSearch : Maelicke_2010_J.Mol.Neurosci_40_135
PubMedID: 19669943

Title : Probing Torpedo californica acetylcholinesterase catalytic gorge with two novel bis-functional galanthamine derivatives - Bartolucci_2010_J.Med.Chem_53_745
Author(s) : Bartolucci C , Haller LA , Jordis U , Fels G , Lamba D
Ref : Journal of Medicinal Chemistry , 53 :745 , 2010
Abstract : N-Piperidinopropyl-galanthamine (2) and N-saccharinohexyl-galanthamine (3) were used to investigate interaction sites along the active site gorge of Torpedo californica actylcholinesterase (TcAChE). The crystal structure of TcAChE-2 solved at 2.3 A showed that the N-piperidinopropyl group in 2 is not stretched along the gorge but is folded over the galanthamine moiety. This result was unexpected because the three carbon alkyl chain is just long enough for the bulky piperidine group to be placed above the bottleneck (Tyr121, Phe330) midway down the gorge. The crystal structure of TcAChE-3 at 2.2 A confirmed that a dual interaction with the sites at the bottom, and at the entrance of the gorge, enhances inhibitory activity: a chain of six carbon atoms has, in this class of derivatives, the correct length for optimal interactions with the peripheral anionic site (PAS).
ESTHER : Bartolucci_2010_J.Med.Chem_53_745
PubMedSearch : Bartolucci_2010_J.Med.Chem_53_745
PubMedID: 20025280
Gene_locus related to this paper: torca-ACHE