Nicotinic receptor modulation: advantages for successful Alzheimer's disease therapy.
Galantamine is a modest acetylcholinesterase inhibitor (AChEI) that is also an allosteric potentiating ligand (APL) of nicotinic acetylcholine receptors (nAChRs). In this report, these two effects are shown to be dependent upon each other using a realistic computer model of the cholinergic synaptic cleft. The model is based upon realistic estimates of the anatomy of a neuronal synapse, the kinetic states of pre- and postsynaptic nAChRs, and the acetylcholinesterase enzyme. The number of open postsynaptic nAChRs per action potential is a measure of cholinergic neurotransmission. Using mathematical equations and published data, the effect of the AChEI and APL actions of galantamine is quantitatively described and compared to the effects of pure AChEIs. The model shows that galantamine--compared to similar concentrations of pure AChEIs--is able to compensate for its somewhat modest effect on the cholinesterase enzyme with its allosteric modulatory effects that include the additional benefit of a lower degree of receptor desensitization.
Geerts
H
H
CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium. Hugo-Geerts@In-Silico-Biosciences.com
Finkel
L
L
Carr
R
R
Spiros
A
A
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D005702:Galantamine / Q000627:therapeutic use*; D006801:Humans; D018697:Nootropic Agents / Q000627:therapeutic use*; D011978:Receptors, Nicotinic / Q000378:metabolism*
D018697:Nootropic Agents; D011978:Receptors, Nicotinic; D005702:Galantamine