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Iloperidone is a novel psychotropic compound currently undergoing Phase III trials. Its affinity for human dopamine and 5-HT receptors has been reported previously (Kongsamut et al. 1996). This report presents the affinity of iloperidone for a largely extended number of human neurotransmitter receptors. In a few instances human receptors were not available and receptor studies were performed on tissues from laboratory animals. The present data, supplemented with those of Kongsamut et al. (1996) The prototypical classical neuroleptic agent haloperidol is an effective antipsychotic compound (Leucht et al. 1999) which, unfortunately, also induces severe extrapyramidal side effects (EPS) and hyperprolactinemia. The term "atypical antipsychotic" was originally introduced to describe compounds, such as clozapine, which not only suppressed psychotic symptoms, but differed from haloperidol by having a low tendency to induce EPS and increase plasma prolactin levels. It is postulated that dopamine D 2 receptor blockade is the mechanism by which antipsychotic activity is achieved (Creese et al. 1976;Seeman et al. 1976 Conley et al. 1999;Taylor and Duncan-McConnell 2000). The elucidation of the multiple receptor interactions of clozapine suggested that other neurotransmitter systems may also play a role in the efficacy and tolerability of that molecule. Particularly, the antiadrenergic effects of clozapine are now receiving increased attention (Nutt 1994;Litman et al. 1996;Hertel et al. 1999). Iloperidone is a new psychotropic agent currently undergoing Phase III trials for the treatment of psychotic disorders (Figure 1). Iloperidone was selected from a large series of piperidinyl-benzisoxazoles because it showed a 300-fold greater potency in a test for limbic activity (inhibition of apomorphine-induced climbing) than in a test for nigrostriatal activity (inhibition of apomorphine-induced stereotypy) . The large difference of potency of iloperidone in these tests is expected to result in an improved ratio of therapeutic effect to EPS liability compared with standard antipsychotics. Previous studies have investigated the receptor binding profile of iloperidone with rat receptors ) and a limited number of human homologues of dopamine and 5-HT receptor subtypes (Kongsamut et al. 1996). These experiments demonstated that iloperidone displays the desired 5-HT 2A /D 2 affinity ratio. The aim of the present study was to determine the receptor affinity profile of iloperidone at a wider range of human neurotransmitter receptors. In resemblance to clozapine, it was noted that iloperidone possesses high affinity for norepinephrine ␣ 1 -and ␣ 2C adrenergic receptors. METHODSThe radioligand receptor binding assays are listed in Table 1. MaterialsRadioligands were purchased from NEN Life Science Products, USA, except for 3 H-RX821002 and 3 H-Mesulergine, which were obtained from Amersham Pharmacia Biotech Ltd, UK, and 125 I-GTI which was obtained from ANAWA, Switzerland. Iloperidone was synthesized by Hoechst Marion Roussel. Unless speci...

A summary of the properties of CGP 51901 is shown in Table 3. On the basis of its binding to IgE and IgE-secreting cells and its activity in vitro and in vivo, CGP 51901 is expected to be able to decrease serum IgE by direct clearance of IgE and by reduction of the numbers and productivity of IgE-secreting cells. The end result of reduction of IgE in the circulation and on mast cells is expected to be the attenuation of IgE-mediated reactions and the improvement in allergy symptoms. The effective serum concentration of CGP 51901 is expected to be in the range 1-10 micrograms/ml. Because CGP 51901 is an antibody specific for IgE, it is expected to be highly selective in its activity. Because IgE does not appear to be essential and because CGP 51901 has been rigorously tested to confirm its non-anaphylactic nature, this treatment is not expected to have any adverse effects. Therefore, CGP 51901 is expected to be safe and to have a good probability of being effective when it is tested in human clinical trials.

The proton magnetic resonance spectra of cation-exchange resins of crosslinkage XI to XI6 in the H +, Li', N a + , K -, R b + , Cs +, and NH,' forms have been recorded and the values of the molal chemical shift, 6, , +O, are found to be -0.321, -0.005,0.041,0.031,0.028,0.015, and 0.00 (assumed) p.p.m./mole, respectively, for the cations. These values are very nearly equal to those observed in corresponding aqueous solutions, indicating that ion-solvent interactions are similar in both the resin matrix and the aqueous solution. The temperature dependence of the chemical shift shows the same trend. The effective hydration numbers calculated from the temperature dependence are 2.0 (4.81 m ) for the H + form, 4.8 (3.25 m) and 3.6 (5.26 177) for the Na' form, 4.4 (3.9 m) for the K + form, and 2.4 (6.18 171) for the Cs+ forsn. The ions in the resin phase behave as solutions of strong electrolyte, which is consistent with the polyelectrolyte gel model for the ion-exchange resin.Canadian Journal of Chemistry, 48, 917 (1970) Introduction Nuclear magnetic resonance (n.1n.r.) has bee11 exte~lsively applied to the study of ionic solvation and three reviews (1-3) serve to indicate the extent and scope of present interest in the field. The n.m.r. studies fall into four categories: measurements of (i) reiaxation times, (ii) peak areas. under suitable, though unfortunately uncommon, conditions, solvent exchange may be slowed down sufficiently to allow the observation of cationic solvation shells, leading to a direct determination of the primary solvation number of the cation (4). In contrast, solvation numbers determined by observation of che~nical shifts in electrolyte solutions have a less obvious sigilificauce, since both cationic and anionic effects contribute to the chemical shift. Malinowski and co-workers (5-7) have performed a series of such experiments, observing the proton chemical shift of aqueous electrolyte solutions a t several temperatures and obtaining an "effective" solvation number.It is of interest to perform similar experiments on ion-exchange resin in as q~~arltitative a manner as possible, so that insight may be gained as t o the environ~iients of the ionic species within the resin.Experimental

Raman spectroscopy in laser-heated diamond anvil cells has been employed to probe the bonding state and phase diagram of dense hydrogen up to 140 GPa and 1,500 K. The measurements were made possible as a result of the development of new techniques for containing and probing the hot, dense fluid, which is of fundamental importance in physics, planetary science, and astrophysics. A pronounced discontinuous softening of the molecular vibron was found at elevated temperatures along with a large broadening and decrease in intensity of the roton bands. These phenomena indicate the existence of a state of the fluid having significantly modified intramolecular bonding. The results are consistent with the existence of a pressure-induced transformation in the fluid related to the presence of a temperature maximum in the melting line as a function of pressure.diamond anvil cell | high pressure | Raman scattering | laser heating | melting T he response of the covalent bond of molecular hydrogen to chemical, density, and thermal perturbations is central to a broad range of problems in the physical sciences. In particular, information on the behavior of hydrogen at very high pressures and variable temperatures is needed to explore the theoretically predicted molecular-atomic transition in the solid (1), the existence of an expanded stability field of the fluid and novel lowtemperature diffusive states (2-4), and the nature of reported transitions in the fluid at megabar pressures (5, 6). Hydrogen is also important for understanding the behavior of materials in general at extreme conditions (7,8). Hydrogen is the most abundant element in the cosmos, and the nature of hydrogen at high temperatures and pressures is crucial for understanding the interiors of large gaseous planets, including exoplanets, and other astrophysical bodies (9, 10). The latter includes detailing the sequence of transitions associated with the onset of nuclear processes in ultrahigh density hydrogen plasmas inside very large astrophysical bodies.There are numerous questions surrounding the behavior of dense hydrogen in the condensed matter domain of megabar (10 11 Pa) pressures and of order 10 3 K temperatures. Experiments and first-principles calculations indicate a temperature maximum in the melting curve as a function pressure near 100 GPa and 1,000 K (11-14). Near 140 GPa and higher temperatures, there is evidence for onset of electrical conductivity (5) and an increase in density (6). The downturn in the melting line has been predicted in various calculations, but the degree of ionization and dissociation in the molecular fluid and an onset of electrical conductivity at higher temperature vary among calculations (15)(16)(17)(18)(19)(20). Characterizing the bonding state of the dense, hot fluid under these conditions is required to search for molecular dissociation and to test competing mechanisms for the onset of electrical conductivity (6,15,17,20,21). The theoretical and experimental indications of a presence of the maximum in the melting line (11,...