PNU-109291

The enantioselective synthesis of isochroman motifs has been accomplished by palladium(II)‐catalyzed allylic C−H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide‐oxazoline (ArSOX) ligand. The allylic C−H oxidation reaction proceeds with the broadest scope and highest levels of asymmetric induction reported to date (avg. 92 % ee, 13 examples with greater than 90 % ee).

Serotonin (5‐HT, 5‐hydroxytryptamine) reduces blood pressure of the conscious rat when administered chronically (1 week). 5‐HTdoes not directly relax isolated arteries, and microsphere experiments in 5‐HT‐infused rats suggested that 5‐HTincreased flow to the splanchnic bed. We hypothesized that 5‐HTincreased splanchnic flow because of direct venous relaxation; our focus was thus on the superior mesenteric vein (SMV) as an important vein in splanchnic circulation. Real‐timeRT‐PCR, immunohistochemistry and Western analyses supported the predominant expression of the 5‐HT2Band 5‐HT7receptor in theSMV. TheSMVwas mounted in tissue baths for measurement of isometric contraction. 5‐HTcaused a concentration‐dependent relaxation of the endothelin‐1 (ET‐1)‐contracted vein. The threshold of 5‐HT‐induced venous relaxation was significantly lower than for 5‐HT‐induced venous contraction (~2 vs. 700 nmol/L, respectively). A series of serotonergic agonists established in their use of receptor characterization was tested, and the following rank order of potency found for agonist‐induced relaxation (receptor selectivity): 5‐CT (5‐HT1/5‐HT7)>5‐HT = LP‐44 (5‐HT7)>PNU109291 (5‐HT1D) = BW723C86 (5‐HT2B). 8‐OH‐DPAT (5‐HT1A/7), CP93129 (5‐HT1B),mCPBG(5‐HT3/4), AS19 (5‐HT7) and TCB‐2 (5‐HT2A) did not relax the isolated vein. Consistent with these findings, two different 5‐HT7receptor antagonists SB 269970 and LY215840 but not the 5‐HT2Breceptor antagonist LY272015 nor the nitric oxide synthase inhibitor LNNA abolished 5‐CT‐induced relaxation of the isolatedSMV. 5‐CT (1 μg kg−1 min−1, sc) also reduced blood pressure over 7 days. These findings suggest that 5‐HTdirectly relaxes theSMVprimarily through activation of the 5‐HT7receptor.