NONCOMPETITIVE AGONISM AT NICOTINIC ACETYLCHOLINE-RECEPTORS - FUNCTIONAL-SIGNIFICANCE FOR CNS SIGNAL-TRANSDUCTION

The alkaloids (-) physostigmine (Phy), galanthamine (Gal) and codeine (God), and several derivatives and homologous compounds, can act as no ncompetitive agonists (NCA) of nicotinic acetylcholine receptors (nACh R) from Torpedo electrocytes, frog and mammalian muscle cells, clonal rat pheochromocytoma cells, cultured hippocampal neurons and several e ctopic expression systems, by interacting with a binding site on the a lpha-subunits of these nAChRs that is insensitive to the natural trans mitter, acetylcholine (ACh), and ACh-competitive agonists and antagoni sts. Several endogenous ligands, including opioid-type compounds, can also act via this site, albeit at higher concentrations than is typica l for the interaction with their cognate receptors. The NCA-evoked res ponses can be observed at the single-channel level but they do not sum mate to significant macroscopic currents, suggesting that the major ro le of NCAs is to act as ''co-agonists'', thereby potentiating nAChR ch annel activation by the natural transmitter. In more general terms, no ncompetitive agonists may constitute part of a ''chemical network'', b y 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 a cting NCAs interesting candidate drugs in the treatment of neurodegene rative diseases.