The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies...

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Mammalian nicotinic acetylcholine receptors: from structure to function.

Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations.

Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application.

http://orphanin.caltech.edu/~lester/world/Reprints%20from%20our%20lab/2004/Lester-TINS-2004.pdf

Cys-loop receptors: new twists and turns

Therapeutic effects of herbal extracts and constituents in animal models of psychiatric disorders.

Galantamine (Reminyl), an approved treatment for Alzheimer9s disease (AD), is a potent allosteric potentiating ligand (APL) of human α3β4, α4β2, and α6β4 nicotinic receptors (nAChRs), and of the chicken/mouse chimeric α7/5-hydroxytryptamine3 receptor, as was shown by whole-cell patch-clamp studies of human embryonic kidney-293 cells stably expressing a single nAChR subtype. Galantamine potentiates agonist responses of the four nAChR subtypes studied in the same window of concentrations (i.e., 0.1–1 μM), which correlates with the cerebrospinal fluid concentration of the drug at the recommended daily dosage of 16 to 24 mg. At concentrations >10 μM, galantamine acts as an nAChR inhibitor. The other presently approved AD drugs, donepezil and rivastigmine, are devoid of the nicotinic APL action; at micromolar concentrations they also block nAChR activity. Using five CHO-SRE-Luci cell lines, each of them expressing a different human muscarinic receptor, and a reporter gene assay, we show that galantamine does not alter the activity of M1–M5 receptors, thereby confirming that galantamine modulates selectively the activity of nAChRs. These studies support our previous proposal that the therapeutic action of galantamine is mainly produced by its sensitizing action on nAChRs rather than by general cholinergic enhancement due to cholinesterase inhibition. Galantamine9s APL action directly addresses the nicotinic deficit in AD.

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Anja Höffle

Papers

Galantamine Is an Allosterically Potentiating Ligand of Neuronal Nicotinic but Not of Muscarinic Acetylcholine Receptors