sabcomeline and 2-ethyl-8-methyl-2-8-diazaspiro(4-5)decane-1-3-dione

After S-AMPA (8.0 mM) lesions to the nucleus basalis and medial septal regions, at the source of the cortical and hippocampal branches of the forebrain cholinergic projection system, rats displayed long-lasting and relatively stable impairment in long-term reference and short-term working memory in both spatial (place) and associative (cue) radial maze tasks. Treatment with four doses of the partial agonist at the M1 cholinergic muscarinic receptor, sabcomeline (formerly known as SB 202026: 0.01-0.156 mg/kg), substantially reduced working and reference memory errors in both tasks in lesioned rats, in a mainly dose-related manner. These effects were more consistent than those found with the direct muscarinic agonist RS86 (0.05-0.781 mg/kg). The performance of non-lesioned controls was largely unaffected by either treatment. These findings are consistent with previous evidence for cholinergic participation in the radial maze deficits induced by excitotoxic lesions to the forebrain cholinergic projection system. They show that with a relatively selective lesion, which respectively, reduced choline acetyltransferase activity to 36.5 and 22.5% of control level in frontal and dorsolateral cortex, and to 61.8 and 69.2% of control level in dorsal and ventral hippocampus, lesioned rats were responsive to pharmacological treatments aimed to enhance cholinergic function by full or partial agonist activity at M1 receptors. Findings that nicotine (0.1 mg/kg) also reduced radial maze errors in the lesioned animals supports the suggestion that lesion-induced deficits in radial maze performance were amenable to improvement by cholinergic receptor manipulation. However, given the potential adverse side effects of full receptor agonists, which nonselectively target cholinergic receptors throughout the organism, the functional efficacy of sabcomeline, which shows regional selectivity for the central M1 receptor subtypes, suggests that deleterious effects of cholinergic depletion on cognition can be counteracted without incurring the risk of unwanted side effects.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Basal Ganglia; Choline O-Acetyltransferase; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Ganglionic Stimulants; Imines; Male; Maze Learning; Muscarinic Agonists; Nicotine; Nicotinic Agonists; Prosencephalon; Quinuclidines; Rats; Rats, Sprague-Dawley; Septal Nuclei; Succinimides; Time Factors

1. Sabcomeline (SB-202026, 0.03 mg kg(-1), p.o.), a potent and functionally selective M1 receptor partial agonist, caused a statistically significant improvement in the performance of a visual object discrimination task by marmosets. No such improvement was seen after RS86 (0.1 mg kg(-1), p.o.). 2. Initial learning, which only required an association of object with reward and an appropriate response to be made, was not significantly affected. Reversal learning, which required both the extinction of the previously learned response and the acquisition of a new response strategy, was significantly improved after administration of sabcomeline (0.03 mg kg(-1), p.o.). 3. Sabcomeline (0.03 and 0.1 mg kg(-1), p.o.) had no significant effect on mean blood pressure measured for 2 h after administration in the conscious marmoset. 4. Sabcomeline (0.03 mg kg(-1), p.o.) caused none of the overt effects such as emesis or behaviours often seen after the administration of muscarinic agonists, e.g. face rubbing and licking. 5. This is the first study to demonstrate cognitive enhancement by a functionally selective M1 receptor partial agonist in a normal (i.e. non-cognitively impaired) non-human primate and this effect was seen at a dose which did not cause side effects. 6. Perseverative behaviour and deficient acquisition of new information are seen in patients with Alzheimer's disease (AD). Therefore the data suggest that sabcomeline might be of therapeutic benefit in the treatment of AD.

Topics: Alzheimer Disease; Animals; Blood Pressure; Callithrix; Female; Imines; Learning; Male; Memory; Muscarinic Agonists; Parasympathomimetics; Pattern Recognition, Visual; Quinuclidines; Receptor, Muscarinic M1; Receptors, Muscarinic; Succinimides

Sabcomeline, (SB-202026 [R-(Z)-alpha-(methoxyimino)-1 -azabicyclo [2.2.2] octane-3-acetonitrile]), a functionally selective muscarinic M1 receptor partial agonist, was tested in rats trained to perform a delayed, reinforced alternation task in a T maze, a test of short-term spatial memory. For comparison the cholinesterase inhibitor tacrine (THA-9-amino- 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 tested and all three compounds were also compared using a conditioned taste aversion (CTA) task. Sabcomeline (0.001-1.0 mg/kg i.p.) significantly reversed the T-maze choice accuracy deficit induced by a 20-s delay at 0.03 and 0.1 mg/kg. RS86 (0.1-3.0 mg/kg i.p.) 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 task at doses approximately 10 times lower than those required to induce conditioned taste aversion. RS86 was equipotent in both tests. These data support the findings of clinical studies which have shown that SB-202026 provides significant symptomatic improvement in patients with probable Alzheimer's disease at doses which do not induce cholinergic side effects.

Topics: Animals; Cholinesterase Inhibitors; Imines; Male; Maze Learning; Muscarinic Agonists; Quinuclidines; Rats; Receptor, Muscarinic M1; Receptors, Muscarinic; Succinimides; Tacrine; Taste