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.

No abstract

Benzopyranoxazine (+)-7 (PD 128907) is the most dopamine (DA) D3 receptor-selective agonist presently known. The only structural feature which distinguishes 7 from the analogous nonselective naphthoxazines is an oxygen atom in the 6-position. To extend this series of tricyclic DA agonists we used a classic bioisoster approach and synthesized thiopyran analogues of 7, which have a sulfur atom in the 6-position. We prepared trans-4-n-propyl-3,4,4a,10b-tetrahydro-2H,5H-[1]benzothiopyrano[4, 3-b]-1,4-oxazin-9-ol (9, trans-9-OH-PTBTO), its enantiomers ((+)-9 and (-)-9), the racemic cis-analogue (10), and the racemic trans-sulfoxide (11) and studied the potency and selectivity for DA receptors of these compounds. As with other rigid DA agonists, the highest affinity for DA receptors resided in one of the enantiomers, in this case the (-)-enantiomer of 9. On the basis of a single-crystal X-ray analysis of a key intermediate, the absolute configuration of (-)-9 was found to be 4aS,10bR, which is homochiral with (+)-(4aR,10bR)-7. In contrast to (+)-7 however, (-)-9 displayed no selectivity for any of the DA receptors. In addition, it has affinity for 5HT1A receptors. (+/-)-cis-4-n-Propyl-3,4,4a,10b-tetrahydro-2H,5H-[1]benzothiopyrano++ +[4,3-b]-1,4-oxazin-9-ol (10), which was expected to be inactive, displayed affinity and selectivity for the DA D3 receptor, whereas the sulfoxide 11 displayed some DA D3 selectivity, but with a lower affinity. Further pharmacological evaluation revealed that (-)-9 is a very potent full agonist at DA D2 receptors and a partial agonist at DA D3 receptors. The cis-analogue (+/-)-10 displayed the same profile, but with lower potency. These findings were confirmed in vivo: in reserpinized rats (-)-9 displayed short-acting activation of locomotor activity (DA D2 agonism) and also lower lip retraction and flat body posture, (5HT1A agonism). Compound (+/-)-10 had no effect on locomotor activity. In unilaterally 6-OH-DA lesioned rats, (-)-9 gave short-acting locomotor activation. Furthermore, in microdialysis studies in rat striatum, (-)-9 potently decreased DA release, confirming its activation of presynaptic DA D2 receptors.

No abstract

A series of 2-aminotetralins, substituted with a methoxy or a hydroxy group on the 5- or 7-position, and with varying N-alkyl or N-arylalkyl substituents, were prepared and evaluated in binding assays for human dopamine (DA) D2, D3, and D4 receptors. Some members of this series were prepared in former studies, but were never tested in vitro with single receptor subtypes, and these were examined again. None of the tested 2-aminotetralins showed high affinity for the dopamine D4 receptor. However, a number of the 2-aminotetralins showed high affinity for both the D2 and the D3 DA receptors, as exemplified by compounds 11-15 and 21-26, while some had a reasonable selectivity for the DA D3 receptors. The affinities of the 2-aminotetralins for the D21, receptor depended on the type of radioligand (agonist or antagonist) used. The agonist affinity data, obtained by using the agonist ligand [3H]N-0437, are thought to be more relevant for calculating DA receptor subtype selectivity.