Haplophyllum buxbaumii has yielded three new lignan type A glucosides: majidine [2], qudsine [3], and arabelline [4], Cleistanthin B [1] is also reported for the first time from this family. Temperature-dependent nmr studies have provided insight into the conformational equilibria existing in 1, 2, and 4.In continuation of our systematic phytochemical investigation of Haplophyllum buxbaumii A. Juss. (Rutaceae) (1), we now report the isolation and structure elucidation of four diphyllin glucosides, three of which (2-4) are new. These are cleistanthin B [1], 4-The bluish fluorescence of the four lignan glucosides under uv light as well as their similar uv spectra (X max 261.6 nm) indicated that all these compounds bear an arylnaphthalene nucleus (2). The acid hydrolysis of the four lignan glucosides afforded the same aglycone, which was identified by spectral data as diphyllin [11] (12). The sugar residues, identified by tic comparison with authentic samples, were found to be glucose of compound 1, apiose and xylose of compound 2, apiose, arabinose, and glucose of compound 3, and arabinose and glucose of compound 4.The uv, ir, ms, and 'H-nmr spectra were reported for cleistanthin B (3). As the 'Hnmr assignments were not fully made, we present in Table 1 the 'H-nmr spectrum with the assignments of the individual aromatic protons. The 13C-nmr chemical shifts and multiplicity assignments of cleistanthin B are shown in Table 2.Compound 2 was assigned the molecular formula C31H32015) positive fabms m!z 645 [M + H]+). The 'H-nmr spectrum of the acetylated derivative 6 of compound 2showed five 3 H singlets in the region between 2.02 and 2.14, corresponding to the aliphatic acetoxy groups, indicating the presence of five aliphatic hydroxyl groups. The 13C-nmr spectrum (DMSO-

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Pulmonary hypertension (PH) is a complex disease comprising a pathologic remodeling and thickening of the pulmonary vessels causing an after load on the right heart ventricle that can result in ventricular failure. Triggered by oxidative stress, episodes of hypoxia, and other undetermined causes, PH is associated with poor outcomes and a high rate of morbidity. In the neonate, this disease has a similar etiology but is further complicated by the transition to breathing after birth, which requires a reduction in vascular resistance. Persistent pulmonary hypertension of the newborn (PPHN) is one form of PH that is frequently unresponsive to current therapies including inhaled nitric oxide (due to lack of proper absorption and diffusion), and other therapeutics targeting signaling mediators in vascular endothelium and smooth muscle. The need for novel agents, which target distinct pathways in pulmonary hypertension, remains. Herein, we investigated the therapeutic effects of novel muscarinic receptor ligand C1213 in models of PH. We demonstrated that via M3 muscarinic receptors, C1213 induced activating‐ eNOS phosphorylation (serine‐1177), which is known to lead to nitric oxide (NO) production in endothelial cells. Using signaling pathway inhibitors, we discovered that AKT and calcium signaling contributed to eNOS phosphorylation induced by C1213. As expected for an eNOS‐stimulating agent, in ex vivo and in vivo models, C1213 triggered pulmonary vasodilation and induced both pulmonary artery and systemic blood pressure reductions demonstrating its potential value in PH and PPHN. In brief, this proof‐of‐concept study provides evidence that an M3 muscarinic receptor functionally selective ligand stimulates downstream pathways leading to antihypertensive effects using in vitro, ex vivo, and in vivo models of PH.

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