Facilitation of acetylcholine release and improvement in cognition by a selective M2 muscarinic antagonist, SCH 72788

Current treatment of Alzheimer's Disease (AD) requires acetylcholinesterase inhibition to increase acetylcholine (ACh) concentrations in the synaptic cleft. Another mechanism by which ACh levels can be increased is blockade of presynaptic M-2 muscarinic autoreceptors that regulate ACh release. An antagonist designed for this purpose must be highly selective for M-2 receptors to avoid blocking postsynaptic M-1 receptors, which mediate the cognitive effects of ACh. Structure-activity studies of substituted methylpiperadines led to the synthesis of 4-[4-[1(S)-[4-[(1,3-benzodioxol-5-yl) sulfonyl]phenyl] ethyl]-3(R)-methyl-1-piperazinyl]-4-methyl-1-(propylsulfonyl)piperidine. This compound, SCH 72788, binds to cloned human M-2 receptors expressed in CHO cells with an affinity of 0.5 nM, and its affinity at M-1 receptors is 84-fold lower. SCH 72788 is a functional M-2 antagonist that competitively inhibits the ability of the agonist oxotremorine-hl to inhibit adenylyl cyclase activity. In an in vivo microdialy sis paradigm, SCH 72788 increases ACh release from the striatum of conscious rats. The compound is also active in a rodent model of cognition, the young rat passive avoidance response paradigm. The effects of SCI-I 72788 suggest that M-2 receptor antagonists may be useful for treating the cognitive decline observed in AD and other dementias. (C) 2001 Elsevier Science Inc. All rights reserved.