Modeling of prolactin response following dopamine Dreceptor antagonists in rats:can it be translated to clinical dosing?

Prolactin release is a side effect of antipsychotic therapy with dopamine antagonists, observed in rats as well as humans. We examined whether two semimechanistic models could describe prolactin response in rats and subsequently be translated to predict pituitary dopamine D2receptor occupancy and plasma prolactin concentrations in humans following administration of paliperidone or remoxipride. Data on male Wistar rats receiving single or multiple doses of risperidone, paliperidone, or remoxipride was described by two semimechanistic models, the precursor pool model and the agonist-antagonist interaction model. Using interspecies scaling approaches, human D2receptor occupancy and plasma prolactin concentrations were predicted for a range of clinical paliperidone and remoxipride doses. The predictions were compared with corresponding observations described in literature as well as with predictions from published models developed on human data. The pool model could predict D2receptor occupancy and prolactin response in humans following single doses of paliperidone and remoxipride. Tolerance of prolactin release was predicted following multiple doses. The interaction model underpredicted both D2receptor occupancy and prolactin response. Prolactin elevation may be deployed as a suitable biomarker for interspecies translation and can inform the clinical safe and effective dose range of antipsychotic drugs. While the pool model was more predictive than the interaction model, it overpredicted tolerance on multiple dosing. Shortcomings of the translations reflect the need for better mechanistic models

Synthesis, structures, and olefin polymerization capability of vanadium(4+) imido compounds with fac-N3 donor ligands.

One-pot reactions of V(NMe2)4 with a range of primary alkyl- and arylamines RNH2 and Me3SiCl afforded the corresponding five-coordinate vanadium(4+) imido compounds V(NR)Cl2(NHMe2)2 [R = 2,6-C6H3(i)Pr2 (1a, previously reported), 2-C6H4(t)Bu (1b), 2-C6H4CF3 (1c), (t)Bu (1d), Ad (Ad = adamantyl, 1e)]. The crystal structures of 1b (two diamorphic forms) and 1c featured N-H...Cl hydrogen-bonded chains. Reaction of 1a-e with the neutral face-capping, N3 donor ligands TACN (TACN = 1,4,7-trimethyltriazacyclononane) or TPM [TPM = tris(3,5-dimethylpyrazolyl)methane] gave the corresponding six-coordinate complexes V(NR)(TACN)Cl2 (2a-e) and V(NR)(TPM)Cl2 (3a-e). The X-ray structures of 2b, 2c, 2d, 3b, 3c, and 3e were determined. When activated with methylaluminoxane, certain of the complexes V(NR)(TPM)Cl2 (3) formed moderately active ethylene polymerization catalysts, whereas none of the compounds V(NR)(TACN)Cl2 (2) were active

A remarkable inversion of structure-activity dependence on imido N-substituents with varying co-ligand topology and the synthesis of a new borate-free zwitterionic polymerisation catalyst.

Ethylene polymerisation productivities of tris(pyrazolyl)methane-supported catalysts [Ti(NR){HC(Me2pz)3}Cl2] show a dramatically different dependence on the imido R-group compared to those of their TACN analogues, attributed to differences in fac-N3 donor topology; when treated with AliBu3, the zwitterionic tris(pyrazolyl)methide compound [Ti(N-2-C6H4tBu){C(Me2pz)3}Cl(THF)] also acts as a highly active, single site catalyst (TACN = 1,4,7-trimethyltriazacyclononane)

Understanding the Behavior of Systems Pharmacology Models Using Mathematical Analysis of Differential Equations: Prolactin Modeling as a Case Study

In this tutorial, we introduce basic concepts in dynamical systems analysis, such as phase‐planes, stability, and bifurcation theory, useful for dissecting the behavior of complex and nonlinear models. A precursor‐pool model with positive feedback is used to demonstrate the power of mathematical analysis. This model is nonlinear and exhibits multiple steady states, the stability of which is analyzed. The analysis offers insight into model behavior and suggests useful parameter regions, which simulations alone could not