A series of 1,3,4-benzotriazepine-based CCK(2) antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of 1,4-benzodiazepine-based CCK(2) antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK(2) receptors to the earlier molecules and are highly selective over CCK(1) receptors.

Cutaneous metastases from solid primary tumours are uncommon. Carcinoma of the breast is the commonest malignancy to metastasize to skin and is usually associated with a local recurrence post therapeutic mastectomy. There are 8 types of cutaneous metastasis related to breast carcinoma which are differentiated on histopathology. Carcinoma en cuirasse, a subtype, clinically presents as a diffuse indurated plaque occasionally accompanied by firm nodules. It characterized by a dense stromal fibrosis and reduced vascularity as well as single filed interstitial tumour infiltrates. Here we report a case of carcinoma en curaisse in a patient with metastatic breast carcinoma.

Background and purpose: N-methyl-D-aspartate Experimental approach:The pharmacological antagonistic profiles of XK1 and XK2 were assessed using in vitro rat primary cerebrocortical neurones and two-electrode voltage clamp on Xenopus oocytes expressing heterologous GluN1/GluN2B receptors. Direct ligand binding was determined using the recombinant amino-terminal domain (ATD) of GluN2B. Key results: XK1 and XK2 effectively protected against NMDA-induced excitotoxicity in rat primary cortical neurones. Low concentrations of XK1 (10 nM) and XK2 (1 nM) significantly reversed neuronal death. Both compounds failed to inhibit currents measured from oocytes heterologously expressing GluN1-1a subunit co-assembled with the ATD-deleted GluN2B subunit. XK1 and XK2 showed specific binding to recombinant protein of GluN2B ATD with low nanomolar affinities. Several residues in the recombinant ATD of GluN2B were identified to be critical for conferring XK1 and XK2 sensitivity. The inhibitory effects of XK1 and XK2 were pH-sensitive, being increased at acidic pH. Conclusions and implications:These results demonstrate that XK1 and XK2 are effective neuroprotective agents in vitro and indicate that 5-substituted benzimidazole derivatives inhibit GluN1/GluN2B receptors via direct binding to the ATD of the GluN2B subunit. These compounds represent valuable alternatives to the classical antagonist ifenprodil as pharmacological tools for studying GluN2B-containing NMDA receptors.