SABCOMELINE (8B-202026), A FUNCTIONALLY SELECTIVE M-1 RECEPTOR PARTIAL AGONIST, REVERSES DELAY-INDUCED DEFICITS IN THE T-MAZE

Sabcomeline, (SB-202026 [R-(Z)-alpha-(methoxyimino)-1-azabicyclo [2.2. 2] octane-3-acetonitrile]), a functionally selective muscarinic M-1 re ceptor partial agonist, was tested in rats trained to perform a delaye d, reinforced alternation task in a T maze, a test of shortterm spatia l memory. For comparison the cholinesterase inhibitor tacrine (THA-9-a mino-1,2,3,4-tetrahydroaminoacridine) and the non-selective muscarinic receptor agonist RS86 (2-ethyl-8-methyl-2,8 diazospiro [4.5]-decane-1 ,3-dione hydrobromide) were also rested and all three compounds were a lso compared using a conditioned taste aversion (CTA) task. Sabcomelin e (0.001-1.0 mg/kg IP) significantly reversed the T-maze choice accura cy deficit induced by a 20-s delay at 0.03 and 0.1 mg/kg. RS86 (0.1-3. 0 mg/kg IP) reversed the deficit at 1.0 mg/kg and THA (0.1-3.0 mg/kg I P) had no effect at any dose. All three compounds induced conditioned taste aversion with minimum effective doses (MED) of 0.3. 1.0 and 3.0 mg/kg, respectively. The results show that sabcomeline reverses delay induced deficits in T-maze choice accuracy in a rewarded alternation t ask at doses approximately 10 times lower than those required to induc e conditioned taste aversion. RS86 was equipotent in both tests. These data support the findings of clinical studies which have shown that S B-202026 provides significant symptomatic improvement in patients with probable Alzheimer's disease at doses which do not induce cholinergic side effects.