The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]-octan-3-amine as a novel, nonpeptide substance P antagonisst.

We describe the structure-activity relationship development of a series of quinuclidines which culminated in the first potent, selective, nonpeptide substance P (SP) antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine, 3 (CP-96,345). Compound 3 is a potent displacer of [3H]SP binding in human IM-9 cells and blocks SP-induced and capsaicin-induced plasma extravasation, as well as SP-induced salivation in the rat in vivo. This compound may both help to further our understanding of the interactions of small molecules with peptide receptors and serve to evaluate the therapeutic potential of a SP antagonist.     

Immunohistologic properties of benign and malignant mixed tumor of the lacrimal gland.

We studied the immunohistopathologic features of normal lacrimal gland, benign mixed tumor, and malignant mixed tumor of the lacrimal gland. Primary antisera were to keratin, muscle-specific actin, vimentin, and glial fibrillary acid protein. Keratin stained in occasional myoepithelial cells in normal gland, ductal epithelium in normal gland and the tumors, and occasional stromal epithelioid cells in the tumors. Muscle-specific actin stained in myoepithelium and vascular smooth muscle in normal gland and the tumors, and occasional spindle-shaped and clusters of stromal cells in the tumors. Vimentin staining was nonspecific. Glial fibrillary acid protein stained in occasional myoepithelial cells in normal gland and polyhedral stromal cells in benign mixed tumor. Our findings indicate that ductal epithelium develops into the epithelial component, and some cells in the stroma and myoepithelium develop into some cells in the stroma of benign and malignant mixed tumor of the lacrimal gland.     

Regional distribution of protease-resistant prion protein in fatal familial insomnia

Protease-resistant prion protein, total prion protein, and glial fibrillary acidic protein were measured in various brain regions from 9 subjects with fatal familial insomnia. Six were homozygotes methionine/methionine at codon 129 (mean duration, 10.7 ± 4 months) and 3 were heterozygotes methionine/valine (mean duration, 23 ± 11 months). In all subjects, protease-resistant prion protein was detected in gray matter but not in white matter and peripheral organs. Its distribution was more widespread than that of the histopathological lesions, which were observed only in the presence of a critical amount of the abnormal protein. In the mediodorsal thalamic nucleus, however, a severe neuronal loss and astrogliosis were associated with relatively moderate amounts of protease-resistant prion protein, suggesting a higher vulnerability. There was no overall correlation between amount of protease-resistant prion protein and either glial fibrillary acidic protein or total prion protein. While protease-resistant prion protein was virtually limited to subcortical areas and showed a selective pattern of distribution in the subjects with disease of the shortest duration, it was more widespread in the subjects with a longer clinical course, indicating that with time the disease process spreads within the brain. The kinetics of the accumulation of protease-resistant prion protein varied among different brain regions: While in the neocortex and to a lesser extent in the limbic lobe and in the caudate nucleus, the amount increased with disease duration, in the mediodorsal thalamic nucleus and in the brainstem it was present in comparable amounts in all subjects regardless of the disease duration. These findings indicate that in fatal familial insomnia, the pathological phenotype is the result of the variability, in different brain regions, of the (1) timing and rate of accumulation of protease-resistant prion protein, and (2) vulnerability to the presence of protease-resistant prion protein.