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The selective D3-dopamine receptor agonist 4aR, 10bR-(+)-trans-3,4,4a, 10b-tetrahydro-4-[N-propyl-2,3-3H]-2H,5H-[1] benzopyrano[4,3-b]-1,4-oxazin-9-ol ([3H]PD 128907) was used to visualise D3-dopamine receptors in whole hemisphere cryosections from post-mortem human brain. [3H]PD 128907 has an 18- to 40-fold selectivity for D3- over D2-dopamine receptors as compared to a 7- to 24-fold selectivity of the more commonly used ligand [3H]7-OH-DPAT. [3H]PD 128907 accumulated markedly in the nucleus accumbens and in the ventral parts of caudate nucleus and putamen, with a slightly heterogeneous (patch-matrix like) distribution. The binding in the lateral parts of caudate nucleus and putamen was much less dense. No binding was obtained in any other regions. A very high proportion of [3H]PD 128907 was specifically bound, as judged from the low binding remaining in the presence of the D2/D3-dopamine receptor antagonist raclopride. This gives the ligand a potential for the detection of low density D3-dopamine receptors in the human brain. The binding obtained with [3H]PD 128907 was qualitatively similar to that using [3H]7-OH-DPAT in the presence of GTP. However, [3H]7-OH-DPAT labelled, in contrast to [3H]PD 128907, also D3-dopamine receptors in neocortex. The new compound [3H]PD 128907 appears to be a suitable radioligand for autoradiographic examination of the D3-dopamine receptor localisation in the human brain, and should also be useful for pharmacological studies of this receptor subtype.

Liquid chromatographic-mass spectrometric (LC-MS) analysis of plasma taken from cynomolgus monkeys dosed orally with (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenylcyclohexen-1- yl)methyl]pyridine (1), a dopamine (DA) autoreceptor agonist and potential antipsychotic agent, revealed several metabolites. The molecular masses of three major metabolites suggested that they were mono- and dihydroxylated derivatives of 1. We synthesized compounds 2 and 3, the two possible mono-p-hydroxyphenyl derivatives of 1, along with the bis-p-hydroxyphenyl derivative 4. These compounds coeluted by HPLC with the three hydroxylated metabolites of 1. Compounds 2-4 all had high affinities for DA D2 and D3 receptors and moderate affinities for D4 receptors. Like 1, compound 2 decreased DA synthesis and neuronal firing in rat brain, indicative of DA autoreceptor activation. Compound 2 inhibited exploratory locomotor activity in rodents and was active in the Sidman avoidance test in squirrel monkeys, predictive of antipsychotic activity in humans. Compounds 3 and 4 showed weak activity in all these tests. After squirrel monkeys were dosed with 1 orally at the ED100 dose of the Sidman avoidance test, the plasma concentration of 2 was below the limit of quantitation. Therefore, these metabolites are unlikely to contribute greatly to the potent activity seen with 1 in the Sidman avoidance test.

PD 128907 [4a R, 10 b R-(+)-trans-3, 4, 4a, 10 b - tetrahydro - 4- n -propyl2 H,5H-[1]benzop-yrano[4,3-b]1,4-oxazin-9-ol.], a selective dopamine (DA) D3 receptor agonist ligand exhibits about a 1000-fold selectivity for human D3 receptors (Ki, 1 nM) versus human D2 receptors (Ki, 1183 nM) and a 10000-fold selectivity versus human D4 receptors (Ki, 7000 nM) using [3H]spiperone as the radioligand in CHO-K1-cells. Studies with [3H]PD 128907, showed saturable, high affinity binding to human D3 receptors expressed in CHO-K1 cells (CHO-K1-D3) with an equilibrium dissociation constant (Kd) of 0.99 nM and a binding density (Bmax) of 475 fmol/mg protein. Under the same conditions, there was no significant specific binding in CHO-K1-cells expressing human D2 receptors (CHO-K1-D2). The rank order of potency for inhibition of [3H]PD 128907 binding with reference DA agents was consistent with reported values for D3 receptors. These results indicate that [3H]PD 128907 is a new, highly selective D3 receptor ligand with high specific activity, high specific binding and low non-specific binding and therefore should be useful for further characterizing the DA D3 receptors.

The enantiomers of reduced haloperidol (3a), azaperol (3b), and the related compound BMY-14802 (3c) were prepared in high optical purity. The affinity of these compounds for dopamine D2 and D3 receptors, and sigma S1 and S2 sites was determined in vitro. Both enantiomers of 3a display greatly decreased affinity for D2 and D3 receptors compared to haloperidol, although they still possess affinities in the 100-200-nM range. Both enantiomers of 3a possess potent and equal affinity for S1 sites (Ki: 1-2 nM), only slightly weaker than haloperidol (Ki: 0.33 nM). At S2 sites, (R)-(+)-3a displays similar affinity to haloperidol (Ki: 31 and 26 nM, respectively), while (S)-(-)-3a is slight more potent (Ki: 8.2 nM). The stereoselectivity profile of the enantiomers of 3b at D2 and D3 receptors is quite similar to that of 3a, (S)-(-)-3b being about 4 times more potent than its enantiomer at both receptors. (R)-(+)-3b binds preferentially to sigma S1 over S2 sites, while (S)-(-)-3b displays the opposite selectivity profile. Both enantiomers of 3c possess very weak affinity for D2 and D3 receptors. In a manner similar to the enantiomers of 3b, the affinity of (R)-(+)-3c is greater for S1 than S2 sites, while (S)-(-)-3c displays the opposite selectivity profile. Following parenteral administration of both enantiomers of 3a, dopamine synthesis and turnover in rat striatum, cortex, and mesolimbic areas were increased, in a manner similar to the effects produced by haloperidol itself. Additional studies will be required to assess with certainty whether the effects were due to the compounds themselves or simply were a consequence of the in vivo oxidation to haloperidol.

The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]-4H-1-benzopyran-4-ones with dopaminergic activity are described. The nature of the arylpiperazine (AP) moiety determines the dopamine (DA) agonist/antagonist character of this series of compounds; when the aryl portion of the AP is unsubstituted the compounds appear to be DA autoreceptor agonists while substituted aryl groups seem to impart DA antagonist activity. A heterocyclic piperazine, 7-[3-[4-(2-pyridinyl)-1-piperazinyl]propoxy]-4H-1-benzopyran-4-one (31, PD 119819) has been identified as an extremely selective DA autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of spontaneous locomotor activity, inhibition of brain DA synthesis, inhibition of brain DA neuronal firing, stereotypy assessment, and reversal of 6-hydroxydopamine (6-OHDA) induced akinesia in rats. In addition, 31 possesses good oral activity in the Sidman avoidance test in squirrel monkeys, a predictor of clinical antipsychotic efficacy. In another primate model, 31 has been found to lack the liability for extrapyramidal side effects observed with currently available antipsychotic drugs.

The synthesis and pharmacological properties of a novel type of [(arylpiperazinyl)alkoxy]anilines with dopaminergic properties are described. One of these compounds, 3-[3-(4-phenyl-1-piperazinyl)propoxy]benzenamine (4c), has been identified as a selective dopamine (DA) autoreceptor agonist in tests that include [3H]haloperidol binding, inhibition of striatal DA synthesis, inhibition of DA neuronal firing, inhibition of spontaneous locomotor activity, and reversal of reserpine-induced depression in rats. In addition, 4c possesses good oral activity in the Sidman conditioned avoidance test in squirrel monkeys, which is indicative of antipsychotic activity. In a primate model, 4c was found to lack the liability for extrapyramidal side effects usually associated with antipsychotic drugs.

The dopamine agonist profiles of 3,4-dihydro-3-(3-dipropylamino)-2H-1-benzopyran-6- and -8-ol (4 and 5, respectively) were examined. Both 4 and 5 exhibited greater relative affinity for receptors labeled with the dopamine agonist ligand [3H]propylnorapomorphine than for those labeled with the dopamine antagonist ligand [3H]haloperidol. Both compounds attenuated the stimulation of brain dopamine synthesis caused by gamma-butyrolactone (GBL) and decreased the firing rate of substantia nigra dopamine neurons in rats. This profile of activity, together with the ability of the dopamine antagonist haloperidol to reverse the inhibition of dopamine neuronal firing, indicate that both compounds are brain dopamine agonists.