M1 Muscarinic Receptor Preferring Drugs

There has been considerable effort in the development of pharmacological agents that selectively act at the M1 muscarinic acetylcholine receptor, in particular M1 mus-carinic agonists. This is, in large part, because of studies indicating that M1 muscarinic acetylcholine receptors are altered in ► Alzheimer's disease and ► schizophrenia (Langmead et al. 2008). Both of these conditions are marked by cognitive deficits and thus there has been an

Muscarinic Cholinergic Receptor Agonists and Antagonists. Fig. 1. Chemical structures of muscarinic M1; M2 and M4 agonists and antagonists.

interest in developing selective M1 muscarinic agonists to alleviate the cognitive deficits in these conditions. A recent double-blind placebo-control study using xanomeline, a muscarinic M1-preferring agonist, in schizophrenic patients showed significant improvement in overall positive and negative symptom ratings, along with enhanced verbal learning with only mild side effects (Shekhar et al. 2008). Several M1 muscarinic-preferring agonists have been developed, which have shown learning and memory benefits in animal models, but overall, have not fared as well in clinical trials (Langmead et al. 2008). This is likely due to the lack of high selectivity for the M1 muscarinic acetylcholine receptor leading to the activation of other muscarinic receptor subtypes and unwanted side effects, e.g., nausea, diarrhea, sweating, and salivation.

Some of the strongest evidence suggesting that M1 muscarinic receptors support learning and memory comes from experiments examining the effects of M1 muscarinic-preferring antagonists in animal models. For example, systemic administration of M1-preferring receptor antagonist, dicyclomine impairs both learning and memory in a variety of behavioral paradigms. Infusions of the M1-preferring antagonist pirenzepine into specific brain regions of the rodent impair learning or memory (Tzavos et al. 2004). Taken together, several experiments indicate that the blockade of M1 muscarinic acetylcholine receptors in various brain areas impairs learning and memory indicating that M1 muscarinic acetylcholine receptors may support several forms of learning and memory.

A main limitation of compounds such as pirenzepine and dicylomine is that they do not exhibit a strong selectivity for M1 muscarinic receptors compared to the other muscarinic receptor subtypes. Another approach to studying muscarinic receptor activity is through the use of snake toxins that bind to specific muscarinic receptor subtypes. Muscarinic-toxin 7 (MT-7) is one such compound that exhibits greater selectivity for the M1 musca-rinic receptor over other subtypes. Because MT-7 acts as a more selective M1 muscarinic receptor antagonist compared to that of pirenzepine and dicyclomine, it has been used to study the role of M1 muscarinic receptors in learning. A recent experiment demonstrated that injections of MT-7 into the rodent dorsomedial striatum does not affect the initial learning of a spatial discrimination, but specifically impairs spatial reversal learning (McCool et al. 2008). Thus, the results from the blockade of M1 muscarinic receptors indicate that this muscarinic receptor subtype is important for learning, memory, and behavioral flexibility.

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