A MODEL FOR THE DOPAMINE D4 PHARMACOPHORE. C. G. Chidester, R. E. TenBrink, J. A. Leiby, M. W. Smith, A. G. Romero, M. D. Ennis, N. B. Ghazal, S. K. Schlachter, C. L. Bergh, T. J. Poel, R. M. Huff, Pharmacia & Upjohn, Kalamazoo, MI 49001, USA
A model for the dopamine D4 pharmacophore that rationalizes differences in affinities and selectivity for D4 over other CNS receptors will be described. The dopamine D4 receptor is an attractive target for antipsychotic drug development because clozapine, an "atypical" neuroleptic, binds to it with high affinity. Clozapine is an atypical dopamine antagonist because it lacks the extrapyramidal side effects and eventual tardive dyskinesias associated with dopamine antagonists that act at the D2 [[opthyphen]]receptor. Although it does have many other side effects, it is not selective for the D4 receptor and the side effects could be due to interactions with other CNS receptors. A selective D4 antagonist could provide an effective treatment for schizophrenia with fewer side effects. U-101387, a highly selective, high affinity antagonist at the D4 receptor is the result of a determined synthetic chemistry effort which was based on an isochroman lead and used cloned receptors to test affinities of analogs. U-101387 is now in Phase I clinical trials.
Models for the D2 and 5HT1A pharmacophores reported
previously were developed using less flexible structures, including tricyclic
angular and linear benzindoles, imidazoquinolinones, benzoquinolines,
ergolines, and amino-tetralins. In this study we considered affinities for the
D4 receptor of structures used to develop the previous models and in
addition we studied ligands in two new series, analogs of either U-101387 or
U-99363. These are highly selective ligands, but many of their analogs do have
affinity for the D2 and 5HT1A receptors. Crystal
structures of several ligands, including U-101387 and analogs of U-99363E were
determined and molecular mechanics calculations were used to verify that
proposed conformations of structures were reasonable. The D4
pharmacophore model is similar to the D2 and 5-HT1A
models previously developed, but has features that help to rationalize the
observed differences in selectivity.
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