PHARMACOLOGICAL CHARACTERIZATION OF U-101387, A DOPAMINE D4 RECEPTOR-SELECTIVE ANTAGONIST

Dopamine D2-like receptors play an important role in the pharmacothera py of psychotic disorders. Molecular and cellular techniques have iden tified distinct gene products (D2-long, D2-short, D3 and D4) displayin g the D2 receptor pharmacology. However, the contribution of each subt ype in antipsychotic effects or their physiological role remain unclea r. Here we describe the pharmacological effects of a selective D4 anta gonist, U-101387. U-101387 displayed moderately high affinity (K-i = 1 0 nM) and selectivity for the dopamine D4.2 receptor expressed in clon al cell lines. It lacked measurable affinity for not only other dopami ne receptors but also noradrenalin, serotonin and histamine receptor f amilies (K-i > 2000 nM). It fully and dose-dependently antagonized qui npirole-induced cAMP inhibition (without producing any effect by itsel f) in stably transfected cells. U-101387 also displayed excellent oral bioavailability, brain penetration and other pharmacokinetic characte ristics. Unlike classical neuroleptics (e.g., haloperidol), U-101387 n either blocked acute behavioral effects of amphetamine or apomorphine nor did it alter spontaneous locomotion by itself. Additionally, U-101 387 was without effect in behavioral and biochemical tests predictive of extrapyramidal and neuroendocrine side effects. Consistent with the lack of autoreceptor function of D4, acute administration of U-101387 failed to alter dopamine neuronal firing by itself or reverse the inh ibition produced by dopamine agonists and to affect monoamine turnover in areas innervated by the mesencephalic or hypothalamic dopamine neu rons. However, U-101387 potently induced c-fos mRNA expression in the infralimbic/ventral prelimbic cortex to a level similar to that produc ed by the atypical antipsychotic, clozapine. This is consistent with t he predominantly cortical distribution of the D4 receptor. Taken toget her, these results demonstrate that the D4-selective antagonist, U-101 387, produces effects that are distinct from those of the nonselective D2 antagonists as well as D3-preferring agents. U-101387 offers a uni que tool to understand the role of dopamine D4 receptors in diseases i nvolving central dopamine systems.