Aug 6, 2008

Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia

Proceedings of the National Academy of Sciences of the United States of America
W Y ChanChristian C Felder

Abstract

Current antipsychotics provide symptomatic relief for patients suffering from schizophrenia and related psychoses; however, their effectiveness is variable and many patients discontinue treatment due to side effects. Although the etiology of schizophrenia is still unclear, a leading hypothesis implicates an imbalanced dopaminergic system. Muscarinic acetylcholine (ACh) receptors regulate dopamine levels in key areas of the brain involved in psychosis, with the M(4) subtype emerging as a key regulator of dopaminergic hyperactivity. Unfortunately, no selective small molecule tools exist to provide pharmacological validation of this hypothesis. Here, we describe the discovery of a small molecule modulator, LY2033298, that is highly selective for human M(4) receptors by virtue of targeting an allosteric site on this receptor. Pharmacological assays confirmed the selectivity of LY2033298 for the M(4) receptor and revealed the highest degree of positive allosteric enhancement of ACh potency thus far identified. Radioligand binding assays also show this compound to directly potentiate agonist binding while having minimal effects on antagonist binding. Mutational analysis identified a key amino acid (D(432)) in the third extracellular ...Continue Reading

Mentioned in this Paper

Antipsychotic Effect
Thiophenes
Allosteric Site
Extracellular
Schizophrenia
Antagonist Muscle Action
Hyperactive Behavior
Brain
Etiology
Antipsychotic Agents

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