Medicinal Chemistry

Metabotropic glutamate receptor subtype 6 (mGluR6) is a Class C type G protein coupled receptor (GPCR) uniquely expressed on retinal bipolar cells. mGluR6 plays a key role in dim-light vision but little is known about its structure and function. Here, we characterized the role of the three transmembrane (TM) cysteines in activation through site-directed mutagenesis. Function of the receptors in cells and membranes was assayed using cAMP and G protein activation, respectively. Cysteine mutants in TM helix V displayed slightly elevated or wild-type like activity. In contrast, all mutations involving the cysteine in TM helix VI lacked agonist response. Our results suggest that TM VI plays a key role in Class C activation similar to that observed in rhodopsin-like (Class A) GPCRs.

A QSAR study was performed on a series of substituted pyrazolone derivatives. The compounds in the selected series were characterized by spatial, molecular and electrotopological descriptors using QSAR module of molecular design suite (V-Life MDS 4.0). In present research paper we reported 2D-QSAR studies of substituted pyrazolone derivatives. Correlations between inhibitory activities and calculated predictor variables were established through partial least square regression (stepwise forward) method.f

SA4503, a potent σ1 receptor agonist, is under study for functional recovery after stroke, and has been tested for treatment of major depression. Recent behavioral studies indicate that SA4503 can also display antagonist properties, and attenuates psychostimulant-induced hyperactivity in animal models. Further, SA4503 labeled with carbon-11 (halflife 20.4 min), or analogs labeled with fluorine-18 (half-life 109.7 min), are useful for PET studies of the σ1 receptor. Analogs labeled with iodine-123 (13.2 h half-life) would have potential as SPECT imaging agents, while analogs labeled with iodine-125 (60.1 d half-life) could be used routinely in laboratory studies. Toward these ends, we describe the synthesis and radiolabeling, as well as in vitro and in vivo binding studies, of two SA4503 analogs where the 4-methoxy group of the dimethoxyphenethyl moiety is replaced by either a (Z)- or (E)-iodoallyloxy substituent. The iodoallyl groups were introduced by base-promoted coupling of stannylated alkylating agents to 4-O-des-methyl-SA4503, followed by iododestannylation with retention of configuration. Both (Z)- and (E)-iodoallyl-SA4503 displayed moderately high affinities for σ1 and σ2 receptors in vitro (Ki values 11-18 nM). The corresponding radioiodinated ligands were prepared in good yields (57-58%), with high purities (>97%) and high specific activities (>2000 mCi/μmol). Both radioligands readily crossed the blood-brain-barrier of mice, although their log D7.4 values of 3.6 were relatively high. Haloperidol pretreatment defined a modest degree of specific binding to σ1 receptors, but only for the [125I]-labeled (E)-isomer in mouse brain (28%) and liver (25%) at 60 min. Thus, these particular radioligands are not well suited to in vivo studies. More significantly, the work shows that σ receptors display substantial tolerance to bulky structural modifications of SA4503, a feature that might aid in the future development of possible therapeutics based on the SA4503 scaffold.

Gugulipid (GL), an extract of Commiphora mukul, has been safely used for thousands of years in the Indian Ayurveda medicine practice for the treatment of different ailments and has been used recently in many clinical trials that focused on its cholesterol-lowering effect. GL has recently been paid great attention for its cancer chemopreventive and chemotherapeutic potential. Z- and E-Guggulsterone have been identified as the major active components of GL. Studies have shown that GL as well as Guggulsterones can inhibit cancer growth in vitro and in vivo and lead to prevention of cancer initiation, promotion and progression. Although the action mechanisms of GL are not completely understood, GL has been revealed as a multitargeted cancer chemopreventive and chemotherapeutic agent. The increased understanding of the anti-cancer activity of GL and its molecular targets would allow us to improve its efficacies in different types of human cancers by single and/or combination strategies.