Compound 186 is a Negative Allosteric Modulator of Dopamine D2 Receptors: Implications for Improving Schizophrenia Therapy

Excessive dopamine transmission in the striatum via the dopamine D2 receptor (D2R) has been implicated in inducing positive symptoms of schizophrenia (such as hallucinations and delusions). While it is known that antipsychotic drugs alleviate these symptoms by blocking the active site of D2R, other drugs such as allosteric modulators can also decrease dopamine’s ability to bind this receptor, by binding to an allosteric site on D2R. We evaluated the ability of a newly synthesized molecule, compound 186, to modulate the binding of tritiated norpropylapomorphine (NPA)—a high-affinity D2R agonist—in the bovine striatum. Through receptor binding assays, we found a significant, dose-dependent decrease in NPA binding with compound 186. Our findings suggest a potential method to treat dopaminergic disorders such as schizophrenia. Because many of the current treatments for schizophrenia that block the active site of D2R can produce severe side effects, it is important to consider using allosteric modulators in place of antagonists.