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Vol. 283, Issue 2, 636-647, 1997

Biological Profile of L-745,870, a Selective Antagonist with High Affinity for the Dopamine D4 Receptor

Smita Patel, Stephen Freedman, Kerry L. Chapman, Frances Emms, Alan E. Fletcher, Mick Knowles, Rosemarie Marwood, George Mcallister, Jan Myers, Shil Patel, Neil Curtis1, Jan J. Kulagowski1, Paul D. Leeson1, Mark Ridgill1, Mike Graham2, Steve Matheson2, Denise Rathbone2, Alan P. Watt2, Linda J. Bristow3, Nadia M. J. Rupniak3, Elizabeth Baskin4, Joseph J. Lynch4 and C. Ian Ragan

Department of Biochemistry & Molecular Biology, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road Harlow, Essex, U.K.

L-745,870,(3-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-1Hpyrollo[2,3-b] pyridine, was identified as a selective dopamine D4 receptor antagonist with excellent oral bioavailability and brain penetration. L-745,870 displaced specific binding of 0.2 nM [3H] spiperone to cloned human dopamine D4 receptors with a binding affinity (Ki) of 0.43 nM which was 5- and 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 receptor subtypes and had moderate affinity for 5HT2, sigma and alpha adrenergic receptors(IC50 < 300 nM). In vitro, L-745,870 (0.1-1 µM) exhibited D4 receptor antagonist activity, reversing dopamine (1 µM) mediated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2) stimulation of [35S] GTPgamma S binding and 3) stimulation of extracellular acidification rate, but did not exhibit any significant intrinsic activity in these assays. Although standard antipsychotics increase dopamine metabolism or plasma prolactin levels in rodents, L-745,870 (<= 30 mg/kg p.o.) had no effect in these assays. The lack of a suitable in vivo assay for D4 receptor activation prompted the use of in vivo surrogate marker assays which confirmed that doses of 5-60 µg/kg L-745,870 would be sufficient to occupy 50% D4 receptors in the brain. These results show that dopamine D4 receptor antagonism in the brain does not result in the same neurochemical consequences (increased dopamine metabolism or hyperprolactinemia) observed with typical neuroleptics.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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