Abstract
To better understand the effects of weak as well as strong agonists at the human α7 nicotinic acetylcholine receptor (human α7 nAChR), the abilities of several classic nAChR agonists to both activate and inhibit (desensitize) the human α7 nAChR expressed in Xenopus oocytes were quantified and compared. Activation was measured during 0.2–20 s agonist application, as required to elicit a peak response. Inhibition was measured as the reduction in the agonist response to 200 μM ACh in the presence of inhibitor during a 5–20 min incubation. Acetylcholine (ACh), (−)-nicotine, (+)-nicotine, and 1,1-dimethyl-4-phenylpiperazinium (DMPP) were 62- to 130-fold more potent as inhibitors than as activators, with excellent correlation between the IC 50 and EC 50 values ( r 2=0.924). Agonist concentrations that elicited only 0.6–1.2% nAChR activation were sufficient to inhibit the response to ACh by 50%. Thus, even a very weak agonist could appear to be a potent and effective inhibitor through receptor desensitization. (−)-Lobeline, in contrast, acted as an antagonist at the human α7 nAChR, eliciting no detectable agonist-like response at concentrations up to 1 mM, but inhibiting the response to ACh with an IC 50 value of 8.5 μM. (−)-Cotinine and the novel ligand ABT-089 [2-methyl-3-(2-( S)-pyrrolidinylmethoxy)pyridine] acted as weak agonists at the human α7 nAChR (1 and 1.5% response at 1 mM, respectively) and inhibited the response to ACh with IC 50 values of 175 and 48 μM, respectively. These effects could be explained by receptor desensitization, at least in part.
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