Clonidine, an antihypertensive drug, binds to alpha 2-adrenergic and imidazoline receptors. The endogenous ligand for imidazoline receptors may be a clonidine-displacing substance, a small molecule isolated from bovine brain. This clonidine-displacing substance was purified and determined by mass spectroscopy to be agmatine (decarboxylated arginine), heretofore not detected in brain. Agmatine binds to alpha 2-adrenergic and imidazoline receptors and stimulates release of catecholamines from adrenal chromaffin cells. Its biosynthetic enzyme, arginine decarboxylase, is present in brain. Agmatine, locally synthesized, is an endogenous agonist at imidazoline receptors, a noncatecholamine ligand at alpha 2-adrenergic receptors and may act as a neurotransmitter.

Two new diketopiperazine dimers, WIN 64821 (la) and WIN 64745 (2), were isolated from an Aspergillus culture originally isolated from soil and their structures established on the basis of chemical and spectroscopic evidence. The dimer la has Cl symmetry with each of two equivalent

Cryptolepine (1) is a rare example of a natural product whose synthesis was reported prior to its isolation from nature. In the previous paper we reported the discovery of cryptolepine's antihyperglycemic properties. As part of a medicinal chemistry program designed to optimize natural product lead structures originating from our ethnobotanical and ethnomedical field research, a series of substituted and heterosubstituted cryptolepine analogues was synthesized. Antihyperglycemic activity was measured in vitro and in an NIDDM mouse model to generate the first structure-bioactivity study about the cryptolepine nucleus.

Three new compounds, named fiscalins A, B, and C, were found in culture broth produced by a Neosartorya fischeri. These compounds inhibit the binding of radiolabeled substance P ligand to the human neurokinin (NK-1) receptor, with Ki values of 57, 174, and 68 |UM, respectively.Detailed spectroscopic and amino acid analyses led to the elucidation of structures for the three fiscalins. Thestructures contain an indolyl moiety linked to an athranilic acid derived tricyclic system. The absolute configuration of fiscalin A was determined by X-ray crystallography and chiral amino acid analysis. The presence of fiscalins was detected directly in crude cellular extracts using LC-MS methods. 545Substance P (SP) is an undecapeptide belonging to a family of related peptides called neurokinins, which act as neurotransmitters and neuromodulators. Cell surface receptors for the neurokinins have been classified into three subtypes, based upon affinities for selective ligands.1* SP is a potent agonist, and believed to be the endogenous ligand for the neurokinin-1 (NK-1) receptor subtype. SP induces a variety of physiological responses such as salivation, vasodilation, smooth muscle contraction, and is thought to be involved in pain transmission and inflammatory response.2) Therefore, selective antagonists of SP might prove to be novel analgesics or anti-inflammatory agents.In order to evaluate the pharmacologic activities of SP antagonists, bioavailable and metabolically stable compoundsare required. Earlier work on SP antagonists generally focused on modifications of the SP peptide, such as described in a recent review.3) More recently, several nonpeptide SP antagonists have been reported, from synthetic4~7) or microbial8) sources, and a microbial cyclic peptide.9'10) These compounds, which varied in structural features, potency and receptor specificities, exhibited activity in various cellular, tissue or in vivo systems, furthering our understanding of the therapeutic potential of SP antagonists.In our search for novel nonpeptide SP antagonists, we wanted to detect compounds active against a NK-1receptor of human origin. Wetherefore screened microbial broth extracts for the ability to inhibit radiolabeled SP binding to human astrocytoma U373M6intact cells, which are a convenient source of the NK-1 receptor subtype. One strain of the fungus, Neosartorya fischeri, produced three new compounds, fiscalins A, B, and C (Fig. 1), which exhibit moderate inhibition of SP binding (Aj=57, 174, and 68piM, respectively). X-ray crystallography, chiral amino acid analysis, and spectroscopy were used to determine the structure of fiscalin A. Structure determination of all three metabolites and their production and biochemical properties are presented herein.

Two new iridoid glycosides (1 and 2), together with the known compounds barlerin (3) and verbascoside (4), were isolated from Barleria prionitis. The new iridoid glycosides were determined to be 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (1) and its cis isomer (2) by using spectroscopic, especially 2D NMR, data. A 3:1 mixture of 1 and 2 was shown to have potent in vitro activity against respiratory syncytial virus (EC50 2.46 microgram/mL, IC50 42.2 microgram/mL).