Minireview: Noncompetitive Agonism at Nicotinic Acetylcholine Receptors; Functional Significance for CNS Signal Transduction

Abstract

The alkaloids (-)physostigmine (Phy), galanthamine (Gal) and codeine (Cod), and several derivatives and homologous compounds, can act as noncompetitive agonists (NCA) of nicotinic acetylcholine receptors (nAChR) from Torpedo electrocytes, frog and mammalian muscle cells, clonal rat pheochromocytoma cells, cultured hippocampal neurons and several ectopic expression systems, by interacting with a binding site on the alpha-subunits of these nAChRs that is insensitive to the natural transmitter, acetylcholine (ACh), and ACh-competitive agonists and antagonists. Several endogenous ligands, including opioid-type compounds, can also act via this site, albeit at higher concentrations than is typical for the interaction with their cognate receptors. The NCA-evoked responses can be observed at the single-channel level but they do not summate to significant macroscopic currents, suggesting that the major role of NCAs is to act as "co-agonists", thereby potentiating nAChR channel activation by the natural transmitter. In more general terms, noncompetitive agonists may constitute part of a "chemical network", by which intercellular messengers, in addition to serving their cognate receptors, could modulate the sensitivity of other neuroreceptors to their archetypic ligands. Such a mode of action would make centrally acting NCAs interesting candidate drugs in the treatment of neuro-degenerative diseases.

Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists

“…Since the smoking status of the schizophrenic subjects treated in the Stryjer et al (2003) and Buchanan et al (2003) studies was not reported the possible confounds of nicotine in these studies cannot be discussed. An alternative to pure cholinesterase inhibitors are drugs like galantamine with a dual mechanism of action including selective competitive inhibition of acetylcholinesterase (Thomsen et al 1991) and allosteric potentiation of nicotinic receptor response (Maelicke et al 1995;Maelicke and Albuquerque 1996;Schrattenholz et al 1996;Samochocki et al 2003). Galantamine interacts with the nicotinic receptor at sites that are different from those for acetylcholine and nicotine where it modulates ion channel activity and potentiates the actions of the nicotinic receptors in the presence of acetylcholine.…”

Increased Levels of Tau Protein in SH‐SY5Y Cells After Treatment with Cholinesterase Inhibitors and Nicotinic Agonists

“…In addition to tacrine, ChEIs like galanthamine, donepezil, and NXX‐066 induce up‐regulation of nAChRs, and they have been suggested to bind to an allosteric site on the nAChR that is distinct from that for acetylcholine (Svensson and Nordberg, 1997). Acting as allosteric ligands, low concentrations of physostigmine and galanthamine when applied with nicotinic agonists increase the frequency of opening of nAChR channels and potentiate agonist‐activated currents (Pereira et al, 1993, 1994; Maelicke et al, 1995; Schrattenholz et al, 1996).…”

Cholinergic abnormalities in Alzheimer's disease: are there new targets for drug development?

“…Interest in nicotinic drugs has followed from the finding that AD patients have decreased levels of cortical nAChRs compared to age-matched controls [Whitehouse et al, 1986;Flynn and Mash, 1986;Aubert et al, 1992]. Apart from their stimulation of ACh-mediated nicotinic receptors, the therapeutic benefit of cholinesterase inhibitors may also be due, at least in part, to the upregulation of nAChRs [Nordberg et al, 1992;Svensson and Nordberg, 1996] and to direct effects on an allosteric site on nAChR that is distinct from that for binding ACh [Pereira et al, 1994;Maelicke et al, 1995;Svensson and Nordberg, 1998]. Activation of presynaptic nAChRs has been shown to increase the release of a number of neurotransmitters that are deficient in patients with AD, including ACh, monoamines, and glutamate [Albuquerque et al, 1997;Levin and Simon, 1998].…”