James P. Guare

Design and synthesis of N-alkylated saccharins as selective α-1a adrenergic receptor antagonists☆

Abstract Benign prostatic hyperplasia can be managed pharmacologically with α-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the α-1 a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective α-1 a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.

A short synthesis of 3(r)-hydroxy-2(R)-isopropyltetrahydrothiophene: A precursor to a high-affinity P2-ligand of HIV-1 protease inhibitors

Abstract The title compound was synthesized in a 6 step sequence involving an efficient lipase-mediated resolution of racemic 3-hydroxy-2-isopropyltetrahydrothiophene.

[3H]L-654,284 as a probe of the central alpha2 adrenoceptor

SummaryL-654,284 ((2R, 12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a]quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide), a potent and selective antagonist of the alpha2 adrenoceptor, was tritiated to high specific activity. Saturation binding to cell membrane suspensions obtained from calf cerebral cortex revealed a high affinity binding site (0.63 nM). Kinetics of association and dissociation were well represented by single exponential processes, and the equilibrium dissociation constant obtained from the ratio of rate constants agreed well with that found by saturation binding. A direct comparison of saturation binding revealed that the antagonist [3H]L-654,284 had roughly the same affinity for the alpha2 adrenoceptor as the agonist [3H]clonidine and eight times the affinity of the antagonist [3H]rauwolseine. The maximum receptor densities of these radioligands were not significantly different. Competition assays with a series of compounds of known receptor affinity revealed that [3H]L-654,284 selectively binds to a site with all of the characteristics expected of the alpha2 adrenoceptor.

Interaction of Mutant Forms of the HIV-1 Protease with Substrate and Inhibitors

The protease of HIV-1 is considered to be a prime target for the treatment of AIDS with small molecular weight inhibitors. 1,2,3 Many groups have now demonstrated that compounds designed as potent inhibitors of the enzyme in vitro are effective inhibitors of viral polyprotein processing and viral spread in cultured cells.4–7 Continued effort to discover new potent inhibitors with suitable properties for use in humans is thus justified.

Fourier Transform Mass Spectrometry and Nuclear Magnetic Resonance Analysis for the Rapid and Accurate Characterization of Hexacosanoylceramide

Ceramides are a central unit of all sphingolipids which have been identified as sites of biological recognition on cellular membranes mediating cell growth and differentiation. Several glycosphingolipids have been isolated, displaying immunomodulatory and anti-tumor activities. These molecules have generated considerable interest as potential vaccine adjuvants in humans. Accurate analyses of these and related sphingosine analogues are important for the characterization of structure, biological function, and metabolism. We report the complementary use of direct laser desorption ionization (DLDI), sheath flow electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) and high-field nuclear magnetic resonance (NMR) analysis for the rapid, accurate identification of hexacosanoylceramide and starting materials. DLDI does not require stringent sample preparation and yields representative ions. Sheath-flow ESI yields ions of the product and byproducts and was significantly better than monospray ESI due to improved compound solubility. Negative ion sheath flow ESI provided data of starting materials and products all in one acquisition as hexacosanoic acid does not ionize efficiently when ceramides are present. NMR provided characterization of these lipid molecules complementing the results obtained from MS analyses. NMR data was able to differentiate straight chain versus branched chain alkyl groups not easily obtained from mass spectrometry.