NEUROPROTECTIVE AND MEMORY-RELATED ACTIONS OF NOVEL ALPHA-7 NICOTINICAGENTS 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 neuroprotective actions associated with both ag onist and antagonist alpha-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 [(125)\]alpha-bungarotoxin bindi ng from rat brain membranes and activated rat alpha-7 receptors in a X enopus oocyte expression system fully efficaciously. The potency serie s for binding and receptor activation was 2-MeOCA > 4-MeOCA = 3-CA and 2-MeOCA = 3-CA > 4-MeOCA, respectively. No compound significantly act ivated oocyte-expressed alpha-4beta-2 receptors. Although each cinnamy lidene-anabaseine caused a longterm inhibition of alpha-7 receptors, a s measured by ACh-application 5 min later, this inhibition ranged cons iderably, from less than 20% (3-CA) to 90% (2-MeOCA) at an identical c oncentration (10 mu M). These compounds improved passive avoidance beh avior in nucleus basalis lesioned rats, with 2-MeOCA most potent in th is respect. In contrast, only 3-CA was neuroprotective against neurite loss during nerve growth factor deprivation in differentiated rat phe ochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist wi thout antagonist activity, was also protective in this model. These re sults suggest that the neurite-protective action of alpha-7 receptor a gonists may be more sensitive to potential long-term antagonist proper ties than acute behavioral actions are.