Synthesis and Pharmacological Evaluation of Thiopyran Analogues of the Dopamine D<sub>3</sub> Receptor-Selective Agonist (4a<i>R</i>,10b<i>R</i>)-(+)-<i>trans</i>-3,4,4a,10b- Tetrahydro-4-<i>n</i>-propyl-2<i>H</i>,5<i>H</i>-[1]benzopyrano[4,3-<i>b</i>]-1,4-oxazin-9-ol (PD 128907)

Benzopyranoxazine (+)-<b>7 </b>(PD 128907) is the most dopamine (DA) D<sub>3</sub> receptor-selective agonist presently known. The only structural feature which distinguishes <b>7</b> 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 <b>7</b>, which have a sulfur atom in the 6-position. We prepared <i>trans</i>-4-<i>n</i>-propyl-3,4,4a,10b-tetrahydro-2<i>H</i>,5<i>H</i>-[1]benzothiopyrano[4,3-<i>b</i>]-1,4-oxazin-9-ol (<b>9</b>, <i>trans</i>-9-OH-PTBTO), its enantiomers ((+)-<b>9 </b>and (−)-<b>9</b>), the racemic <i>cis</i>-analogue (<b>10</b>), and the racemic <i>trans-</i>sulfoxide (<b>11</b>) 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 <b>9</b>. On the basis of a single-crystal X-ray analysis of a key intermediate, the absolute configuration of (−)-<b>9 </b>was found to be 4a<i>S</i>,10b<i>R</i>, which is homochiral with (+)-(4a<i>R</i>,10b<i>R</i>)-<b>7</b>. In contrast to (+)-<b>7</b> however, (−)-<b>9</b> displayed no selectivity for any of the DA receptors. In addition, it has affinity for 5HT<sub>1A</sub> receptors. (±)-<i>cis</i>-4-<i>n</i>-Propyl-3,4,4a,10b-tetrahydro-2<i>H</i>,5<i>H</i>-[1]benzothiopyrano[4,3-<i>b</i>]-1,4-oxazin-9-ol <b>(10)</b>, which was expected to be inactive, displayed affinity and selectivity for the DA D<sub>3</sub> receptor, whereas the sulfoxide <b>11 </b>displayed some DA D<sub>3</sub> selectivity, but with a lower affinity. Further pharmacological evaluation revealed that (−)-<b>9 </b>is a very potent full agonist at DA D<sub>2</sub> receptors and a partial agonist at DA D<sub>3</sub> receptors. The <i>cis-</i>analogue (±)-<b>10</b> displayed the same profile, but with lower potency. These findings were confirmed in vivo:  in reserpinized rats (−)-<b>9 </b>displayed short-acting activation of locomotor activity (DA D<sub>2</sub> agonism) and also lower lip retraction and flat body posture, (5HT<sub>1A</sub> agonism). Compound (±)-<b>10</b> had no effect on locomotor activity. In unilaterally 6-OH-DA lesioned rats, (−)-<b>9 </b>gave short-acting locomotor activation. Furthermore, in microdialysis studies in rat striatum, (−)-<b>9 </b>potently decreased DA release, confirming its activation of presynaptic DA D<sub>2</sub> receptors.