SCH 57790:: A novel M2 receptor selective antagonist

As a decrease in cholinergic neurons has been observed in Alzheimer's Disease (AD), therapeutic approaches to AD include inhibition of acetylcholinesterase to increase acetylcholine levels. Evidence suggests that acetylcholine release in the CNS is modulated by negative feedback via presynaptic M-2 receptors, blockade of which should provide another means of increasing acetylcholine release. Structure-activity studies of [4-(phenylsulfonyl)phenyl]methylpiperazines led to the synthesis of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl] -phenyl]-1-piperazineacetonitrile. This compound, SCH 57790, binds to cloned human M-2 receptors expressed in CHO cells with an affinity of 2.78 nM; the affinity at M-1 receptors is 40-fold lower. SCH 57790 is an antagonist at M-2 receptors expressed in CHO cells, as the compound blocks the inhibition of adenylyl cyclase activity mediated by the muscarinic agonist oxotremorine. This compound should be useful in assessing the potential of M-2 receptor blockade for enhancement of cognition.