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The synthesis and pharmacological activity of a new seriesof 1-arylpyrazoles as potent σ1receptor (σ1R) antagonists are reported. The new compounds were evaluatedin vitro in human σ1R and guinea pig σ2receptor (σ2R) binding assays. The natureof the pyrazole substituents was crucial for activity, and a basicamine was shown to be necessary, in accordance with known receptorpharmacophores. A wide variety of amines and spacer lengths betweenthe amino and pyrazole groups were tolerated, but only the ethylenoxyspacer and small cyclic amines provided compounds with sufficientselectivity for σ1R vs σ2R. Themost selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed highactivity in the mouse capsaicin model of neurogenic pain, emergedas the most interesting candidate. In addition, compound 28exerted dose-dependent antinociceptive effects in several neuropathicpain models. This, together with its good physicochemical, safety,and ADME properties, led compound 28to be selected asclinical candidate. [ABSTRACT FROM AUTHOR]

A series of new N1-, N2- and N3-substituted 1,2,3-triazole derivatives has been synthesized by cycloaddition of butyltin azide with substituted alkynes followed by a N-alkylation reaction. The regioisomers have been isolated and characterized using NMR techniques. GIAO/B3LYP calculations of the absolute shieldings have been performed to verify the assignments and so the structures have been unequivocally identified. The proportion in which the three isomers are obtained corresponds with the relative order of stability indicated by the energy values calculated at the B3LYP level. CB1 cannabinoid receptor binding assays have been performed but none of the compounds showed significant activity. [ABSTRACT FROM AUTHOR]

The synthesis of a new series of 4-acylaminopyrazolo[3,4- d ]pyrimidines active on the sigma-1 receptor (σ 1 R) is reported. Compounds were efficiently prepared using a two to three step process starting from commercially available 1 H -pyrazolo[3,4- d ]pyrimidin-4-amine. A SAR study shows that the σ 1 R requires the presence of relatively highly lipophilic substituents at opposite sides of the central scaffold, while selectivity versus the σ 2 R can be improved by shortening the distance of the basic nitrogen to it. Compound 9a was among the most active and selective in vitro derivatives and exhibited potent antinociceptive properties in several pain models in mice, indicating its antagonistic behaviour.

Neoadjuvant chemoradiation therapy is one of the standard therapeutic regimens for rectal carcinoma. Nevertheless, chemoradiation therapy is not completely devoid of adverse effects, and it would be interesting to try to predict which patient will respond to neoadjuvancy. This study aimed at analyzing factors influencing pathological response after therapy. We reviewed the clinical and morphological data of 39 patients after neoadjuvant chemoradiation therapy. We performed immunohistochemistry for p53, cyclin D1, MIB-1 (Ki67), and bcl-2 protein in paraffin-embedded tissue. In our series, 12 patients did not respond to neoadjuvant therapy, 12 showed a complete response, and 15 a partial response. There was a statistically significant association between response and cardiomyopathy (p=0.02) and tenesmus (p=0.02) and a trend towards significance for age (p=0.08), preoperative TNM (p=0.08), peritumoral inflammatory response (p=0.07), and preoperative CEA (p=0.08). As for immunohistochemistry, we only found a trend towards significance for cyclin D1 (p=0.08). In our series of patients with rectal carcinoma receiving preoperative chemoradiation therapy, few factors were predictive of a histological response. The histological response seems to improve survival and reduce relapses.