SELECTIVE DOPAMINE D-4 RECEPTOR ANTAGONISTS

The discovery that the atypical antipsychotic clozapine has higher aff inity for the dopamine D-4 receptor relative to the D-2 receptor touch ed off a search for more potent, highly selective D-4 antagonists as a new class of antipsychotics. Many compounds achieving high potency an d selectivity are now available including L-745,870 (Merck), NGD 94-1 (Neurogen), PNU-101,387 (Pharmacia & Upjohn), CP-293,019 (Pfizer), and PD-172,938 (Warner-Lambert). Unfortunately, L-745,870 did not improve psychotic symptoms in a Phase II clinical trial, causing many researc hers to question the role of the D-4 receptor in the aetiology of schi zophrenia. Recent findings with new biological models and D-4 selectiv e agonists may help clarify D-4 receptor physiology.