We report on the pharmacological effects of the 20 fold D3 vs. D2 dopamine receptor preferring compound U99194A. It is shown that U99194A increases rat locomotor activity at doses that do not increase release or utilisation of dopamine in the striatum or the nucleus accumbens significantly. The data do not support any direct agonist action of U99194A at dopamine receptors. It is suggested that U99194A can antagonise a population of postsynaptic dopamine receptors involved in the suppression of some aspects of psychomotor activity. These postsynaptic receptors presumably belong to the D3 receptor subtype.

To establish possible functional differences between the dopamine D2 and D3 receptor we investigated the relation between the ability, for a set of nine mixed dopamine D2 and D3 receptor antagonists, to displace N, N-dipropyl-2-amino-5,6-dihydroxy tetralin (DP-5,6-ADTN) from striatal binding sites and the subsequent behavioural consequences in vivo. Dopamine D2 receptor preferring antagonists are powerful displacers of DP-5,6-ADTN from the striatum. Maximal displacement is followed by strong hypomotility. Displacement of the agonist by the D3 preferring antagonist U99194A is only partial and results in synergistic increases in locomotor activity. Superimposing haloperidol upon GBR12909 leads to a synergistic increase in striatal dialysate dopamine concentrations. This effect is absent when combining GBR12909 with the putative D3 antagonist U99194A. These data give support for the hypothesis that the dopamine D3 receptor is functionally relevant at the postsynaptic level. Here, in contrast to the D2 receptor, it is proposed to exert an inhibitory influence on psychomotor functions.

Conformational and molecular mechanics studies of a new series of tricyclic ligands with affinity for either the dopamine D2 receptor or the 5-HT1A receptor, or both, has enabled us to elaborate considerably on previous pharmacophore models for these receptors. The new tricyclic ligands are either angular, 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives, or linear, 2,3,3a,4,5,9a-hexahydro-1H-benz[f]indole derivatives; they have either cis or trans ring junctions, and many of the ligands are resolved. In order to have X-ray crystal coordinates for every structural type, two additional crystal structures were determined: 14a, the trans-(+-)-6-hydroxy-3-(n-propyl) angular derivative as the hydrochloride, and (+-)-1,2,2a,3,4,8b-hexahydro-8-methoxy-2-(2-propenyl)-naphth[2,1- b]azetidine hydrochloride (16d). Several recently reported imidazoquinolinones with dopaminergic and serotonergic activities were also used in developing the models as were other known ligands which are conformationally constrained. A new method for determining intrinsic activity at the D2 receptor made consistent and reliable estimates of dopamine agonist, partial agonist, and antagonist activities available. The models explain these activities in terms of the 3-dimensional structural features of the ligands and their probable orientations at the D2 receptor site. They also explain why allyl and propyl analogs of some structures have very different affinities while affinities are quite similar for allyl and propyl analogs of other structures; at both receptors a particular orientation of the amine substituent in the binding site correlates with preference for allyl over propyl derivatives. Suggestions are made for enhancing selectivity at the 5-HT1A receptor or at the dopamine D2 receptor. An angular, cis, (3aR,9bS), 2-propyl, 9-hydroxy, 3-(n-propyl) analog should be selective for the 5-HT1A receptor. A linear, trans, (3aR,9aS), 7-hydroxy, 1-(2-propenyl) analog should be selective for the dopamine D2 receptor, and would be predicted to be an antagonist.

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