Dopamine D4 receptor antagonists

Interest in the dopamine D4 receptor has arisen primarily as a result of the observation that the atypical antipsychotic agent clozapine (2) binds to this novel receptor with higher affinity when compared to the other dopamine receptor subtypes and that at therapeutic doses, clozapine occupies the majority of central D4 receptors, but not D2 receptors. Further reports, although both currently controversial, that D4 receptors were elevated in postmortem schizophrenic brains and that they exhibited a preferential limbic distribution in the CNS stimulated a search to identify novel D4 receptor selective antagonists as potential clozapine-like atypical antipsychotics. A number of structurally diverse compounds, exhibiting varying degrees of affinities and selectivities for the D4 receptor have been identified and are discussed in this review. Three of these compounds, namely 9 (NGD 94-1, Neurogen/Schering Plough), 17 (L-745,870, Merck), and 40 (U-101,387, Pharmacia and Upjohn), have been or are currently being evaluated in man, and a brief synopsis of their preclinical, and, where appropriate, their clinical findings is included.