Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.

In response to various exogenous stimuli, mast cells (MCs) release a wide variety of inflammatory mediators stored in their cytoplasmic granules and this release initiates subsequent allergic reactions. Lysophosphatidylserine (lysoPS) has been known as an exogenous inducer to potentiate histamine release from MCs, though even at submicromolar concentrations. In this study, through SAR studies on lysoPS against MC degranulation, we identified lysoPT, a threonine-containing lysophospholipid and its 2-deoxy derivative as novel strong agonists. LysoPT and its 2-deoxy derivative induced histamine release from MCs both in vitro and in vivo at a concentration less than one-tenth that of lysoPS. Notably, lysoPT did not activate a recently proposed lysoPS receptor on MCs, GPR34, demonstrating the presence of another undefined receptor reactive to both lysoPS and lysoPT that is involved in MC degranulation. Thus, the present strong agonists, lysoPT and its 2-deoxy derivative, will be useful tools to understand the mechanisms of lysoPS-induced activation of degranulation of MCs.

Design, synthesis, and BK channel-opening activity of hexahydrodibenzazepinone derivatives.

In order to explore new scaffolds for large-conductance Ca2+ -activated K+ channel (BK channel) openers, we carried out molecular design and synthesis on the basis of the following two concepts: (1) introduction of a heteroatom into the dehydroabietic acid (BK channel opener) skeleton would allow easier introduction of substituents. (2) Because of the fourfold symmetrical structure of BK channels, dimeric compounds in which two pharmacophores are linked through a tether are expected to have a greater binding probability to the channels, resulting in increased channel-opening activity. Herein, we explore the usefulness of the hexahydrodibenzazepinone structure as a new scaffold for BK channel openers. The synthesized monomer compounds of hexahydrodibenzazepinone derivatives, which can be derived from dehydroabietic acid, were subjected to electrophysiological patch-clamp studies, followed by Magnus contraction-relaxation assay using rabbit urinary bladder smooth muscle strips to assess overall activities. Dimeric compounds were designed by linking the monomeric hexahydrodibenzazepinone derivatives through a diacetylenebenzene tether, and their channel-opening activities were evaluated by electrophysiological methods. Finally, we concluded that the critical structure for BK channel-opening activity is the hexahydrodibenzazepinone monomer substituted with a phenyl-bearing alkynyl substituent on the lactam amide.

Molecular mechanisms for large conductance Ca2+-activated K+ channel activation by a novel opener, 12,14-dichlorodehydroabietic acid.

Our recent study has revealed that 12,14-dichlorodehydroabietic acid (diCl-DHAA), which is synthetically derived from a natural product, abietic acid, is a potent opener of large conductance Ca(2+)-activated K(+) (BK) channel. Here, we examined, by using a channel expression system in human embryonic kidney 293 cells, the mechanisms underlying the BK channel opening action of diCl-DHAA and which subunit of the BK channel (alpha or beta1) is the site of action for diCl-DHAA. BK channel activity was significantly enhanced by diCl-DHAA at concentrations of 0.1 microM and higher in a concentration-dependent manner. diCl-DHAA enhanced the activity of BKalpha by increasing sensitivity to both Ca(2+) and membrane potential without changing the single channel conductance. It is notable that the increase in BK channel open probability by diCl-DHAA showed significant inverse voltage dependence, i.e., larger potentiation at lower potentials. Since coexpression of beta1 subunit with BKalpha did not affect the potency of diCl-DHAA, the site of action for diCl-DHAA is suggested to be BKalpha subunit. Moreover, kinetic analysis of single channel currents indicates that diCl-DHAA opens BKalpha mainly by decreasing the time staying in a long closed state. Although reconstituted voltage-dependent Ca(2+) channel current was significantly reduced by 1 microM diCl-DHAA, BK channels were selectively activated at lower concentrations. These results indicate that diCl-DHAA is one of the most potent BK channel openers acting on BKalpha and a useful prototype compound to develop a novel BK channel opener.

Compounds structurally related to tamoxifen as openers of large-conductance calcium-activated K+ channel.

We found that a variety of compounds containing partial structures of tamoxifen showed activity as chemical modulators of large-conductance calcium-activated K+ channels (BK channels).

A phthalocyanine dendrimer capable of forming spherical micelles.

A novel and intrinsically spherical micelle has been prepared by utilizing a silicon phthalocyanine ((WG3)SiPc) that has a thin hydrophobic alkyl chain and a bulky hydrophilic poly(aryl ether) dendrimer with terminal carboxyl groups, as its two axial ligands. Gel-permeation chromatography and cryo-transmission electron microscopic experiments indicate that (WG3)SiPcs self-assemble to form a spherical micelle at very low concentrations in aqueous solution. Depending on the pH of the aqueous phase, (WG3)SiPc shuttles between aqueous and organic phases. In the presence of hydrophobic molecules, this transfer is accompanied by the inclusion of these (guest) molecules, indicating that the micelle acts as a molecular capsule with a nanospace surrounded by functional phthalocyanine planes.

Dehydroabietic acid derivatives as a novel scaffold for large-conductance calcium-activated K+ channel openers.

We found that the dehydroabietic acid structure is a new scaffold for chemical modulators of large-conductance calcium-activated K+ channels (BK channels). Structure-activity relationship (SAR) studies of the dehydroabietic acid derivatives and related non-aromatic compounds such as pimaric acid revealed the importance of the carboxyl functionality and an appropriate hydrophobic moiety of the molecules for BK channel-opening ability.

A Novel Hemiporphyrazine Comprising Three Isoindolediimine and Three Thiadiazole Units.

Incorporation of three metal ions (Ni or Cu) in the macrocyclic ring and the formation of hexamers following a 3+3 approach are novel features of the hemiporphyrazines (one example shown) formed by the condensation of 2,5-diamino-1,3,4-triazole with isoindolediimines. This is in contrast to the corresponding reactions with diaminotriazoles, which afford 2+2 products.