Structural requirements for competitive s-adrenoceptor occupancy bycyclic and opened analogues of WB 4I0I

Modification of WB-4101 led to the discovery of several analogues with alpha adrenergic antagonist activity with comparable affinities

ANALYSIS OF CARBAMATE AND PHENYLUREA PESTICIDE RESIDUES IN FRUIT JUICES BY SOLID-PHASE MICROEXTRACTION AND LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY

A new analysis method to detect carbamates and phenylurea pesticide residues in fruit juices was developed using solid-phase microextraction (SPME) coupled with liquid chromatography–single quadrupole mass spectrometry (LC/MS) and liquid chromatography–quadrupole ion trap mass spectrometry (LC/QIT-MS). The pesticide residues present in watery matrices as fruit juices were extracted using three types of fibers: 50-μm Carbowax/templated resin (CW/TPR), 60-μm poly(dimethylsiloxane)/divinylbenzene (PDMS/DVB) and 85-μm polyacrylate. The different extraction conditions were evaluated choosing as the best parameters 90 min (time), 20 °C (temperature) and 1 ml (volume). After extraction, the desorption (in a static mode) was performed in the specific interface chamber SPME/HPLC, previously filled with 70% methanol and 30% water. The best recoveries, evaluated at two fortification levels (0.2 and 0.5 mg kg−1) in fruit juices, were obtained using PDMS/DVB and CW/TPR fibers, and ranged from 25 to 82% (monolinuron, diuron and diethofencarb), with relative standard deviations (RSDs) from 1 to 17%. All the limits of quantification (LOQs) were in the range of 0.005–0.05 μg ml−1 and, in any case, equal to, or lower than, maximum residue limits (MRLs) established by Italian and Spanish legislations. The mass spectrometry analyses were carried out using an electrospray ionization (ESI) source operating in the positive mode both for single quadrupole and for QIT mass analysers, operating in selected ion monitoring (SIM) and in multiple reaction monitoring (MRM) modes, respectively. The proposed new method can be applied to the determination of selected pesticides in real samples of fruit juices

Synthesis and alpha-blocl\uabing activity of some cyclicand opened analogues of WB 4101 (-)

The synthesis of some cyclic and opened analogues of 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane (1, WB 4101) is described. The blocking activity of 1-5 was determined on the pre- and postsynaptic alpha-adrenoceptors of isolated rat vas deferens to investigate the structural requirements for competitive alpha-adrenoceptor occupancy by antagonists of the benzodioxane class. The activities of 1-5 at the presynapticalpha-adrenoceptor were not signiflcantly different whereas there were differences among the compounds of at least two orders of magnitudeat the postsynaptic alpha-adrenoceptor. This clearly indicates that the shuctural requirements at the presynaplic receptor level are less restriclive than those required by the postsynaptic alpha-adrenoceptor. The symmetric analogues 3 and 4 were significantly weaker postsynaplic alpha-antagonists compared to 1. On the other hand, 2 and 5 displayed a very high postsynaptic activity, almost comparable to that of 1. Th\ue8se findingi might suggest that the antagonists of the benzodioxane class do not bind at two identical aromalic sites symmetrically arranged around the anionic site of the alpha-adrenoceptor. Indeed, they might indicate that the benzodioxane binding site(s) incorporates two areas with very similar but not identical strLrctural requirements. Furthermore, the very high activity of 5 may suggest that the benzodioxane nucleus is not essential to activity

Structure-activity relationships among novel phenoxybenzamine-related beta-chloroethylamines

A series of beta-chloroethylamines 5–18, structurallyrelated to the irreversible a1-adrenoceptor antagonist phenoxybenzamine [PB, N-benzyl-N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)amine hydrochloride, 1] and the competitive antagonist WB4101 [N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N-[2-(2,6-dimethoxyphenoxy)ethyl]amine hydrochloride, 2], were synthesized and evaluated for their activityat a-adrenoceptors of the epididymal and the prostatic portion of young CD rat vas deferens. All compounds displayed irreversible antagonist activity. Most of them showed similar antagonism at both alpha1- and alpha2-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate alpha1-adrenoceptor selectivity(10–35 times), which was comparable to that of PB. Compounds 14 and 15, belonging to the benzyl series and bearing, respectively, alpha 2-ethoxyphenoxy and a 2-i-propoxyphenoxy moiety, were the most potent alpha1-adrenoceptor antagonists with an affinityvalue similar to that of PB (pIC50 values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two a1-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these a1-adrenoceptors was determined from compounds 8–10, 12, and 15–17. Furthermore, compounds 9, 10, 12, 16a, and 16b showed higher affinitytowards the minor population of receptors, whereas compounds 8, 15, and 17 preferentiallyinhibited the major population of alpha1-adrenoceptors. In addition, selected pharmacological experiments demonstrated the complementaryantagonism of the two series of compounds and their different, preferential affinity for one of the two alpha 1-adrenoceptor subtypes. In conclusion, we found beta-chloroethylamines that demonstrate a multiplicity of alpha1-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for alpha1-adrenoceptor characterization