BIOLOGICAL PROFILE OF L-745,870, A SELECTIVE ANTAGONIST WITH HIGH-AFFINITY FOR THE DOPAMINE-D4 RECEPTOR

L-745,870, orophenyl)piperazin-1-yl]methyl}-1H-pyrollo[2,3-b] pyridine , was identified as a selective dopamine D4 receptor antagonist with e xcellent oral bioavailability and brain penetration. L-745,870 displac ed specific binding of 0.2 nM [H-3] spiperone to cloned human dopamine D4 receptors with a binding affinity (K-i) of 0.43 nM which was 5- an d 20-fold higher than that of the standard antipsychotics haloperidol and clozapine, respectively. L-745,870 exhibited high selectivity for the dopamine D4 receptor (>2000 fold) compared to other dopamine recep tor subtypes and had moderate affinity for 5HT2, sigma and alpha adren ergic receptors (IC50 < 300 nM). In vitro, L-745,870 (0.1-1 mu M) exhi bited D4 receptor antagonist activity, reversing dopamine (1 mu M) med iated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2 ) stimulation of [S-35] GTP gamma S binding and 3) stimulation of extr acellular acidification rate, but did not exhibit any significant intr insic activity in these assays. Although standard antipsychotics incre ase dopamine metabolism or plasma prolactin levels in rodents, L-745,8 70 (less than or equal to 30 mg/kg p.o.) had no effect in these assays . The lack of a suitable in vivo assay for D4 receptor activation prom pted the use of in vivo surrogate marker assays which confirmed that d oses of 5-60 mu g/kg L-745,870 would be sufficient to occupy 50% D4 re ceptors in the brain. These results show that dopamine D4 receptor ant agonism in the brain does not result in the same neurochemical consequ ences (increased dopamine metabolism or hyperprolactinemia) observed w ith typical neuroleptics.