M4 Muscarinic Receptor Preferring Drugs

The M4 muscarinic acetylcholine receptor is another mus-carinic acetylcholine receptor subtype in which there is significant interest in developing selective agents to generate novel treatments for both ► schizophrenia and

► Parkinson's disease. Despite interest in the M4 musca-rinic acetylcholine receptor, there are a relative lack of compounds that are highly selective for this muscarinic receptor subtype. Comparable to developing new targets for the M1 muscarinic receptor, the development of positive allosteric modulators for the M4 muscarinic receptor holds promise in generating novel treatments for various disorders and diseases.

Interest in the M4 muscarinic acetylcholine receptor related to schizophrenia has evolved from findings indicating hyperactivity of the neurotransmitter dopamine in the striatum is observed in schizophrenia (Langmead et al. 2008). Moreover, the activation of M4 muscarinic acetylcholine receptors may inhibit striatal dopamine efflux. PTAC and BuTAC are two compounds that are M4-preferring agonists. These drugs have shown to reduce apomorphine-induced ► prepulse inhibition (Jones et al. 2005), a paradigm commonly used to screen the effectiveness of antipsychotic drugs. As with many other muscarinic agonists, these drugs do not display a strong selectivity for theM4 muscarinic acetylcholine receptor (Langmead et al.

2008). Therefore, there is a real possibility of producing unwanted side effects with such treatments.

Interest in the M4 muscarinic acetylcholine receptor related to ► Parkinson's disease is also related to dopaminergic-cholinergic interactions in the striatum. Owing to the reduced striatal dopamine activity in Parkinson's disease, treatment with a M4 muscarinic ace-tylcholine receptor antagonist may have benefits in enhancing dopaminergic transmission and reducing symptoms in the disease. In support of that idea, tropicamide, a musca-rinic acetylcholine receptor antagonist with moderate binding selectivity for the M4 muscarinic acetylcholine receptor subtype, suppresses tremulous jaw movements in rats, a model of Parkinson's disease, without significant impairment on memory tasks (Betz et al. 2007). Several other compounds that have a high affinity for the M4 mus-carinic acetylcholine receptor and show selectivity over other muscarinic acetylcholine receptor subtypes may prove beneficial in the treatment of Parkinson's disease (Bohme et al. 2002).

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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