Synthesis and structure-activity relationships of a new series of antiarrhythmic agents: 4,4-disubstituted hexahydro-3H-pyrido[1,2-c]pyrimidin-3-ones and related compounds.

A series of 4,4-disubstituted tetrahydro- and 4,4-disubstituted hexahydro-3H-pyrido[1,2-c]pyrimidin-3-ones (4 and 5, respectively) were prepared from 2-aryl-2-(2-piperidinyl)-4-[N,N-bis (1-methylethyl)amino] butanamides (2). Individual racemates of the piperidinyl amides 2 were converted to pure racemic diaza bicyclic compounds that were evaluated for antiarrhythmic activity in the Harris dog model and anticholinergic activity in a muscarinic receptor binding assay. Selected compounds were subsequently evaluated for hemodynamic effects in anesthetized dogs where blood pressure depression and negative inotropic activity were assessed. Of this group, 4a (R = CH3) and 5a (R = CH3) showed the most favorable pharmacological profiles; the former compound was chosen for toxicity testing over the latter due to its lack of noncompetitive inhibition of acetylcholine-induced contractions of guinea pig ileum segments. Clinical evaluation is now under way.

Functionalized graphene sheets for polymer nanocomposites.

Polymer-based composites were heralded in the 1960s as a new paradigm for materials. By dispersing strong, highly stiff fibres in a polymer matrix, high-performance lightweight composites could be developed and tailored to individual applications. Today we stand at a similar threshold in the realm of polymer nanocomposites with the promise of strong, durable, multifunctional materials with low nanofiller content. However, the cost of nanoparticles, their availability and the challenges that remain to achieve good dispersion pose significant obstacles to these goals. Here, we report the creation of polymer nanocomposites with functionalized graphene sheets, which overcome these obstacles and provide superb polymer-particle interactions. An unprecedented shift in glass transition temperature of over 40 degrees C is obtained for poly(acrylonitrile) at 1 wt% functionalized graphene sheet, and with only 0.05 wt% functionalized graphene sheet in poly(methyl methacrylate) there is an improvement of nearly 30 degrees C. Modulus, ultimate strength and thermal stability follow a similar trend, with values for functionalized graphene sheet- poly(methyl methacrylate) rivaling those for single-walled carbon nanotube-poly(methyl methacrylate) composites.

Orientational order of molecular assemblies on inorganic crystals.

Surfactant micelles form oriented arrays on crystalline substrates although registration is unexpected since the template unit cell is small compared to the size of a rodlike micelle. Interaction energy calculations based on molecular simulations reveal that orientational energy differences on a molecular scale are too small to explain matters. With atomic force microscopy, we show that orientational ordering is a dynamic, multimolecule process. Treating the cooperative processes as a balance between van der Waals torque on a large, rodlike micellar assembly and Brownian motion shows that orientation is favored.

Membrane potential-dependent effects of SC-36602, a new class I antiarrhythmic agent on cardiac action potentials.

The in vitro electrophysiological properties of a new class I antiarrhythmic agent, SC-36602, were evaluated by recording action potentials (APs) from guinea pig papillary muscle. SC-36602 and its (+) and (-) enantiomers (10(-6)-10(-4) M) caused a concentration- and only slight frequency-dependent depression of Vmax (maximum rate of rise of the AP). At stimulation rates of 30, 60, 120, and 200 pulses/min, SC-36602 (10(-4) M) reduced Vmax to 64 +/- 2.2, 62 +/- 2.8, 60 +/- 2.4, and 58 +/- 2.7% of control, respectively, and significantly shortened effective refractory period (ERP) (20-40%). The rate constants for onset of block of Vmax during trains of stimuli at 1 or 3.3 Hz were similar (approximately 0.2 AP-1). Slow recovery from Vmax block following a stimulus train recorded in tissue depolarized by 10 mM [K+]o Tyrode's solution was enhanced following exposure to SC-36602. The normalized relationship between Vmax and membrane potential was shifted 3 and 12 mV in the hyperpolarizing direction at stimulation frequencies of 0.2 and 1 Hz, respectively. These results suggest that SC-36602 would preferentially depress conduction in depolarized tissue in vivo.

Redifferentiation and subsequent dedifferentiation of the livers of roosters resulting from acute estrogen challenges.

1. Histologic and metabolic changes take place in livers of rooster receiving challenges consisting of acute doses of estrone. 2. During initial Growth and Redifferentiation livers rapidly increase in size by division of hepatocytes within most lobules, changing from cordlike to acinar configurations. 3. No new lobules appear and degeneration of some cells within lobules takes place even as cell divisions predominate. 4. Cells within lobules assume secretory features. 5. Vitellogenins, very low density lipoproteins, calcium and alkaline phosphatase increase greatly in plasma. 6. Within 35-40 days of cessation of estrogen, livers have returned to near normal sizes and plasmas exhibit normal parameters.