1 TRPM8 (CMR1) is a Ca 2 þ -permeable channel, which can be activated by low temperatures, menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type-1 (VR1, TRPV1). We tested whether substances which are structurally related to menthol, or which produce a cooling sensation, could activate TRPM8, and compared the responses of TRPM8 and VR1 to these ligands. 2 The effects of 70 odorants and menthol-related substances on recombinant mouse TRPM8 (mTRPM8), expressed in HEK293 cells, were examined using a FLIPR s assay. In all, 10 substances (linalool, geraniol, hydroxycitronellal, WS-3, WS-23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists. 3 The EC 50 values of the agonists defined their relative potencies: icilin (0.270.1 mM)4FrescolatML (3.371.5 mM) 4 WS-3 (3.771.7 mM) (À)menthol (4.171.3 mM) frescolatMAG (4.871.1 mM) 4 cooling agent 10 (672.2 mM) (þ )menthol (14.471.3 mM) 4 PMD38 (3171.1 mM) 4 WS-23 (4477.3 mM) 4 Coolact P (66720 mM) 4 geraniol (5.971.6 mM) 4 linalool (6.772.0 mM) 4 eucalyptol (7.772.0 mM) 4 hydroxycitronellal (19.672.2 mM). 4 Known VR1 antagonists (BCTC, thio-BCTC and capsazepine) were also able to block the response of TRPM8 to menthol (IC 50 : 0.871.0, 3.571.1 and 1871.1 mM, respectively). 5 The Ca 2 þ response of hVR1-transfected HEK293 cells to the endogenous VR1 agonist Narachidonoyl-dopamine was potentiated by low pH. In contrast, menthol-and icilin-activated TRPM8 currents were suppressed by low pH. 6 In conclusion, in the present study, we identified 10 new agonists and three antagonists of TRPM8. We found that, in contrast to VR1, TRPM8 is inhibited rather than potentiated by protons.

Galantamine (Reminyl), an approved treatment for Alzheimer's disease (AD), is a potent allosteric potentiating ligand (APL) of human ␣3␤4, ␣4␤2, and ␣6␤4 nicotinic receptors (nAChRs), and of the chicken/mouse chimeric ␣7/5-hydroxytryptamine 3 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 M), which correlates with the cerebrospinal fluid concentration of the drug at the recommended daily dosage of 16 to 24 mg. At concentrations Ͼ10 M, 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. Galantamine's APL action directly addresses the nicotinic deficit in AD.

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Galantamine (ReminylTM) is a novel drug treatment for mild to moderate Alzheimer's disease (AD). Originally established as a reversible inhibitor of the acetylcholine‐degrading enzyme acetylcholinesterase (AChE), galantamine also acts as an allosterically potentiating ligand (APL) on nicotinic acetylcholine receptors (nAChR). Having previously established this second mode of action on nAChRs from murine brain, we demonstrate here the same action of galantamine on the most abundant nAChR in the human brain, the α4/β2 subtype. This nAChR‐sensitizing action is not a common property of all, or most, AChE inhibitors, as is shown by the absence of this effect for other therapeutically applied AChE inhibitors including tacrine, metrifonate, rivastigmine and donepezil. The possible benefits for therapy of AD of an APL action on nicotinic receptors is discussed.

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