Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties

The goals of this study were to develop compounds that were selective and highly efficacious agonists at alpha-7 receptors, while varying in antagonist activity; and to test the hypothesis that these compounds had memory-related and neuroprotec-tive actions associated with both agonist and antagonist al-pha-7 receptor activities. Three compounds were identified; E,E-3-(cinnamylidene)anabaseine (3-CA), E,E-3-(2-methoxy-cinnamylidene) anabaseine (2-MeOCA) and E,E-3-(4-methoxy-cinnamylidene) anabaseine (4-MeOCA) each displaced [125I]a-bungarotoxin binding from rat brain membranes and activated rat alpha-7 receptors in a Xenopus oocyte expression system fully efficaciously. The potency series for binding and receptor activation was 2-MeOCA. 4-MeOCA 5 3-CA and 2-MeOCA 5 3-CA. 4-MeOCA, respectively. No compound significantly activated oocyte-expressed alpha-4beta-2 recep-tors. Although each cinnamylidene-anabaseine caused a long-term inhibition of alpha-7 receptors, as measured by ACh-application 5 min later, this inhibition ranged considerably, from less than 20 % (3-CA) to 90 % (2-MeOCA) at an identical con-centration (10 mM). These compounds improved passive avoid-ance behavior in nucleus basalis lesioned rats, with 2-MeOCA most potent in this respect. In contrast, only 3-CA was neuro-protective against neurite loss during nerve growth factor de-privation in differentiated rat pheochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist without antagonist ac-tivity, was also protective in this model. These results suggest that the neurite-protective action of alpha-7 receptor agonists may be more sensitive to potential long-term antagonist prop-erties than acute behavioral actions are. Molecular, biochemical and physiological studies demon-strate the presence of multiple nicotinic receptor subunits i