Dopamine D₄ Receptors and Schizophrenia: An Unhappy Ending?

Tremendous interest in the dopamine D₄ receptor subtype was generated when it became clear that the atypical antipsychotic drug clozapine binds to it with particularly high affinity. These data, along with the distribution of the D₄ receptor in the brain, suggested that a selective D₄ receptor antagonist was a suitable target for new antipsychotic drug development. In fact, a novel D₄ receptor antagonist was thought to be the long, sought-after antipsychotic with a low propensity for side effects and the potential for greater efficacy. This paper reviewed the experience of the Merck, Sharp, and Dohme research teams with L-745,870, a selective dopamine D₄ receptor antagonist.

L-745,870 has a very high affinity for cloned human D₄ receptors (5…